Preface
Since its inception in 2004, the ‘Clinical Practice Guidelines for the Treatment of
Diabetes’ has attempted to promote evidence‐based, rational, efficient and standardized
clinical practice for diabetes in Japan and has undergone revisions every 3 years.
Thus, the current edition represents the fifth revision.
Of note, in recent years, breakthroughs have been made in the management of diabetes
and its complications, which include the approval of glucose‐lowering agents with
novel mechanisms of action for clinical use and the introduction and adoption of novel
diagnostic and therapeutic modalities, such as continuous glucose monitoring (CGM)
and sensor‐augmented insulin pumps (SAP), in clinical practice. Again, renewed interest
in diabetes‐associated diseases has led to the accumulation of new evidence, as well
as new developments at the Japan Diabetes Society (JDS), such as ongoing efforts directed
toward the revision of the Classification of Diabetic Nephropathy, ensuring consistency
between glucose metabolic disorders and the diagnostic criteria for diabetes in pregnancy,
and establishing glycemic control goals for older patients with diabetes. Indeed,
these developments have gone hand in hand with the emergence of high‐quality evidence
from numerous studies conducted in countries throughout the world, including Japan.
Thus, the current edition aims to incorporate these new insights and findings, as
well as new lines of evidence, in diabetes treatment.
With regard to the revision of the guideline, the current edition has newly adopted
a clinical question (CQ)/question (Q) format, instead of the ‘statement’ format of
the earlier editions, in the hope that this new format will help improve the ease
of use of the guidelines in clinical practice. The grades of recommendation have also
been revised.
It is hoped that the current guidelines will serve as a guide to implementing evidence‐based
medicine (EBM) for diabetes in Japan and thereby contribute to prolonging the longevity
and improving the quality of life (QOL) of patients with diabetes.
Methods for Developing the ‘Japanese Clinical Practice Guideline for Diabetes 2016’
The present guideline, which is divided into 21 chapters, consists of important statements
intended to assist in clinical practice, which are also intended as recommendations.
These statements were developed separately as general questions and clinical questions
based on published clinical evidence as well as expert consensus.
This guideline offers key recommendations for clinical practice that are supported
by scientific evidence from published studies. Studies of interest were obtained by
a systematic search of the English and Japanese literature. The electronic databases
used for literature search included at least MEDLINE and the Japanese ICHUSHI database
(http://www.jamas.or.jp/). The search strategies used were developed by each author.
The studies of interest were critically appraised by the authors to determine their
relevance to the statements of the guideline and whether they were worth citing. Each
study was assigned a level of evidence using the approach described in Table 1.
Table 1
Criteria for assigning levels of evidence to publications of interest
Level of evidence
Type of evidence
1+
High‐qualitya randomized controlled trials (RCTs)
Meta‐analysis or systematic review of trials with level 1+
1
RCTs that fail to meet level 1+ evidence
Meta‐analysis or systematic review of trials with level 1
2
Prospective cohort studies, or meta‐analysis or systematic review of them
Pre‐specified sub‐analyses of RCTs
3
Non‐randomized controlled trials
Self‐controlled (before‐after) studies
Retrospective cohort studies
Case–control studies, or meta‐analysis or systematic review of them
Post‐hoc sub‐analyses of RCTs
4
Cross‐sectional studies
Case‐series
a
A high‐quality RCT was defined as a trial that was appropriately designed and conducted
with a large sample size and a clearly specified randomization scheme, involving double
masking and a high follow‐up rate.
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Each statement for the CQs was assigned a grade of recommendation based on the total
body of evidence as well as the risk‐benefit balance, value, patient preferences,
cost, and resources. Statements were graded as A (strongly recommended) or B (recommended),
followed by the agreement rate among authors. Grade A or B by consensus reflects a
recommendation based solely on the consensus of professionals and indicates that the
recommendation was adopted with a ≥70% agreement rate among the authors.
A summary table, including an identifier, the research design, the level of evidence
and population, methods, and results of the cited articles was attached at the end
of each chapter in the original Japanese version (The Japan Diabetes Society: Japanese
Clinical Practice Guideline for diabetes 2016. Tokyo: Nankodo, 2016.). Scientific
reports supporting a statement were cited as ‘References’ and additional guidelines
or review articles were listed as ‘Additional reference materials’.
The guideline will be reviewed every 3 years, as there will be considerable advances
in clinical research and practice that will require a re‐evaluation of the scientific
evidence as it becomes available. All potential conflicts of interest were disclosed
by authors.
1
Guideline for the Diagnosis of Diabetes Mellitus
Q1‐1 How is diabetes diagnosed? (Figure 1)
Figure 1
Flow chart outlining the steps in the clinical diagnosis of diabetes mellitus. OGTT,
Oral glucose tolerance test.
The diagnosis of diabetes mellitus should be as comprehensive as possible. It is confirmed
by the presence of chronic hyperglycemia, and by the presence of other factors, such
as associated symptoms, clinical laboratory findings, a family history of diabetes,
and the patient's body weight history1, 2, 3, 4, 5. For the diagnosis of diabetes,
either of the following approaches is to be followed:
1
①Two assessments of the diabetic type in each patient (one blood glucose test is mandatory).
2
②One assessment of the diabetic type (with mandatory blood glucose testing) along
with the presence of chronic hyperglycemic symptoms*. (*typical symptoms of chronic
hyperglycemia (e.g., dry mouth, polyposia, polyuria, body weight loss, or diabetic
retinopathy).
3
③Evidence of a prior diagnosis of ‘diabetes’.
Q1‐2 How is hyperglycemia assessed? (Figure 2)
Figure 2
The categories of glycemia as indicated by fasting plasma glucose levels and 75 g
OGTT results. *1 The impaired fasting glucose (IFG) category represents cases of fasting
plasma glucose levels of 110–125 mg/dL (6.1–7.0 mmol/L) and 2‐h plasma glucose levels
of <140 mg/dL (7.8 mmol/L) in a 75 g OGTT (WHO). However, in the ADA criteria, IFG
is defined as a fasting plasma glucose levels of 100–125 mg/dL (5.6–7.0 mmol/L), and
only FPG is used for the determination of IFG. *2 Fasting plasma glucose levels of
100–109 mg/dL (5.6–6.1 mmol/L) are within the normal limits, but are considered to
be ‘high‐normal’. Because patients with a high‐normal glucose level are at risk of
developing diabetes and include cases with various degrees of impaired glucose tolerance,
the performance of an OGTT is desirable. *3 The category was adopted by the WHO in
the diagnostic criteria for diabetes mellitus, and represents cases with fasting plasma
glucose levels of <126 mg/dL and 2‐h plasma glucose levels of 140–199 mg/dL (7.8–11.1
mmol/L in a 75 g OGTT.
Patients are to be classified into the normal type, borderline type, or diabetic type,
based on the combination of fasting and 2‐h post‐75 g oral glucose tolerance test
(OGTT) glucose values.
Patients whose fasting glucose values are 100–109 mg/dL (5.6–6.1 mmol/L) are classified
into the ‘high normal’ category as part of the normal type6.
The OGTT is to be proactively considered in high‐risk individuals (i.e., those who
are suspected to have diabetes or the borderline type, those whose fasting glucose
values are shown to be ‘high‐normal’, those with HbA1c values of ≥5.6%, those with
obesity or dyslipidemia, and those with a strong family history of diabetes5).
At present, HbA1c values measured by point‐of‐care testing (POCT) devices are not
to be used for the diagnosis5.
Q1‐3 How should individuals who are shown to be the diabetic type in an initial glucose/HbA1c
assessment but who not on subsequent assessments be managed?
When the diagnosis is not confirmed by repeated assessments, glucose measurements
and OGTTs should be performed every 3 to 6 months to monitor their clinical course5.
If the glucose value on the initial assessment was found to be ≥200 mg/dL (11.1 mmol/L)
by a casual blood glucose measurement, it would be preferable to use other tests on
the subsequent confirmatory assessments5.
In principle, confirmatory assessments should involve both HbA1c and blood glucose
measurements. The diagnosis must be made with close attention given to their blood
glucose values, particularly in patients with any disease or condition that is likely
to result in disparity between the HbA1c level and the mean glucose value5.
Q1‐4 How is diabetes classified into its types? (Table 2)
Table 2
Etiological classification of diabetes mellitus and glucose metabolism disorders
I. Type 1 (destruction of pancreatic β‐cells, usually leading to absolute insulin
deficiency)
A. Autoimmune
B. Idiopathic
II. Type 2 (ranging from predominantly insulin secretory defect to predominantly insulin
resistance with varying degrees of insulin secretory defect)
III. Due to other specific mutation or diseases
A. Those in which specific mutations have been identified as cause of genetic susceptibility
(1) Genetic abnormalities of pancreatic β‐cell function
(2) Genetic abnormalities of insulin action
B. Those associated with other diseases or conditions
(1) Diseases of exocrine pancreas
(2) Endocrine disease
(3) Liver disease
(4) Drug‐ or chemical‐induced
(5) Infections
(6) Rare forms of immune‐mediated diabetes
(7) Various genetic syndromes often associated with diabetes
IV. Gestational diabetes mellitus
The occurrence of diabetes specific complications has not been confirmed in some of
these conditions. Those that cannot currently be classified as any of the above are
considered unclassifiable.
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The classifications of diabetes are to be primarily described according to the etiology
(mechanism), and additionally according to the pathophysiological state (stage) based
on the insufficiency of insulin action (See Q1‐7 for the relationship between their
etiology and pathophysiology).
Diabetes and other glucose metabolic disorders are to be classified into four categories:
(I) type 1 diabetes, (II) type 2 diabetes, (III) other types due to specific pathophysiological
mechanisms or diseases, and (IV) gestational diabetes (GDM). At present, all forms
of diabetes or other glucose metabolic disorders that fail to be classified as any
of the above are to be classified as ‘unclassifiable’5.
The etiological factors of patients should be assessed with attention to various types
of clinical information such as the family history, age at the onset of diabetes and
clinical course, physical characteristics, islet autoantibodies, human leukocyte antigen
(HLA), insulin‐secretory capacity/severity of insulin resistance, and genetic test
results5.
Individual patients may have multiple etiological factors5.
Q1‐5 How is type 1 diabetes (including acute, slowly‐progressive, and fulminant forms
of type 1 diabetes) diagnosed? (Table 3)
Table 3
Diagnostic criteria for acute‐onset, slowly‐progressive, and fulminant type 1 diabetes
(findings of relevance shown in square brackets)
Criteria
Acute‐onset type 1 diabetes
Slowly‐progressive type 1 diabetes (SPIDDM)
Fulminant type 1 diabetes
1. Symptoms of hyperglycemia and ketoacidosisa
Affected individuals are expected to present with thirst, polydipsia, and polyuria,
leading to the onset of ketosis or ketoacidosis within about 3 months of disease onset
Affected individuals are expected to present with ketosis or ketoacidosis at disease
onset or diagnosis but do not require insulin therapy immediately
Affected individuals are expected to present with thirst, polydipsia, and polyuria
leading to the onset of ketosis or ketoacidosis within about 1 week of onset of hyperglycemia;
they are also expected to present with ketosis at initial consultation
2. Glycemic status/Need for insulin therapy
Affected individuals are expected to require continuous insulin therapy from early
after diagnosis of diabetes; they may also be expected to experience a transient ‘honeymoon
phase’b
Favorable glycemic control can often be achieved without insulin therapy in affected
individuals at an early phase, but insulin therapy is considered effective in slowing
their progression to an insulin‐dependent state
Affected individuals are expected to have casual blood glucose values 288 mg/dL v(16.0
mmol/L) or higher and HbA1c values <8.7% [thus necessitating initiation of insulin
therapy]
3. Islet autoantibodiesc
Affected individuals are expected to be confirmed positive for either GAD antibodies,
IA‐2 antibodies, IAA, or ZnT8 antibodies during their clinical course (IAA positivity
only to be confirmed prior to initiation of insulin therapy)
Affected individuals are expected to be confirmed positive for either GAD antibodies
or ICA during their clinical course
[Generally, affected individuals are expected to test negative for islet autoantibodies]
4. Endogenous insulin secretion
Affected individuals may not be confirmed positive for islet autoantibodies but are
expected to have fasting serum C‐peptide values <0.6 ng/mL thus suggesting a deficit
in endogenous insulin secretion
[Some of these individuals may not show evidence of decreased endogenous insulin secretion,
irrespective of their autoantibody values]
Affected individuals are expected to have urinary C‐peptide values <10 μg/day at disease
onset or fasting serum C‐peptide values <0.3 ng/mL and post‐glucagon load (or 2‐h
postprandial) C‐peptide values <0.5 ng/mL
Diagnosis
Individuals who have met the above criteria 1–3 are to be diagnosed with acute‐onset
(autoimmune) type 1 diabetes.
Those who have met the above criteria 1, 2, and 4 are to be diagnosed with acute‐onset
type 1 diabetes.
Those who have met the above criteria 1 and 2 but not 3 and 4 are to be re‐evaluated
after an interval with the diagnosis put on hold.
Those who have met the criteria for fulminant type 1 diabetes are to be diagnosed
as such
Individuals who have met the above criteria 1 and 3 are to be diagnosed with slowly‐progressive
type 1 diabetes
Individuals who have met the above criteria 1, 2 and 4 are to be diagnosed with fulminant
type 1 diabetes
Other relevant 7findings
Individuals with single‐gene disorders, such as HNF‐1α gene, mitochondrial gene, KCNJ11
gene mutations, are to be excluded from assessment
Insulin therapy may be initiated in affected individuals from early after diagnosis
while they are still not in an insulin‐dependent state
Some individuals may present with thirst, polydipsia, and polyuria leading to the
onset of ketosis or ketoacidosis within about 1–2 weeks of onset of hyperglycemia.
The onset of fulminant type 1 diabetes may be associated with pregnancy.
Exocrine pancreatic enzymes are shown to be elevated in 98% of affected individuals.
Upper airway and gastrointestinal symptoms are noted in 70% of affected individuals.
Fulminant type 1 diabetes is shown to be linked to HLA DRB1*04:05‐DQB1*04:01
a
Ketosis, diagnosed when individuals are found positive for urinary ketone bodies or
associated with increased serum ketone levels.
b
Honeymoon phase, defined as a phase during which glycemic control may be achieved
without insulin therapy for months after initial insulin therapy implemented early
after diagnosis.
c
Islet autoantibodies include glutamic acid decarboxylate (GAD) antibodies, insulinoma‐associated
protein‐2 (IA‐2) antibodies, insulin autoantibodies (IAA), zinc transporter 8 (ZnT8)
antibodies, and islet cell antibodies (ICA) (adapted from7, 8, 9, 10).
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Type 1 diabetes is classified by the etiology as (A) autoimmune and (b) idiopathic
and also classified by the manner of the disease onset as acute, slowly‐progressive,
and fulminant.
Patients with acute type 1 diabetes are generally likely to develop ketosis or ketoacidosis
within 3 months of the onset of hyperglycemia and required insulin therapy immediately7.
Patients with slowly progressive (insulin‐dependent) type 1 diabetes do not develop
ketosis or ketoacidosis and do not require insulin therapy immediately, although their
diagnosis is established by a positive test for anti‐GAD antibodies or islet cell
antibodies (ICA)8.
Patients with fulminant type 1 diabetes frequently develop ketosis or ketoacidosis
within 1 week of the onset of hyperglycemia, require insulin therapy immediately,
and are characterized by having lower HbA1c values relative to their glucose values9.
Q1‐6 How is diabetes due to other specific pathophysiological mechanisms or diseases
diagnosed?
Recent advances in gene analysis techniques have led to a number of single gene abnormalities
being identified as causes of diabetes. These are generally divided into ① those related
to the pancreatic β‐cell function and ② those related to the mechanisms of insulin
action.
A diabetic condition may occasionally be a part of various diseases, syndromes and
pathologies. Some of these were formerly called ‘secondary diabetes’ and include forms
of diabetes associated with pancreatic, endocrine and hepatic diseases, drug use,
exposure to chemicals, viral infections, and an array of genetic syndromes.
Gestational diabetes mellitus (GDM) refers to a form of glucose metabolic disorder
that is detected or which occurs for the first time during pregnancy and does not
reach the criteria of overt diabetes.
The diagnosis of these forms of diabetes requires a close review of relevant clinical
data, which include: ① family history and mode of inheritance; ② age at the onset
of diabetes and clinical course; ③ other physical characteristics; and ④ islet autoantibodies.
Q1‐7 How do the types of diabetes (their etiology) each relate to their respective
pathophysiology (clinical stage)? (Figure 3)
Figure 3
A schematic diagram of the relationship between the etiology (mechanism) and pathophysiological
stages (states) of diabetes mellitus. Arrows pointing right represent the worsening
of glucose metabolism disorders (including the onset of diabetes mellitus). Among
the arrow lines, indicates the condition classified as ‘diabetes mellitus’. Arrows
pointing left represent improvement in the glucose metabolism disorder. The broken
lines indicate events of low frequency. For example, in type 2 diabetes mellitus,
infection can lead to ketoacidosis and require temporary insulin treatment for survival.
Also, once diabetes mellitus has developed, it is treated as diabetes mellitus regardless
of the improvement in the glucose metabolism; thus, the arrow lines pointing left
are filled in black. In such cases, a broken line is used, because complete normalization
of the glucose metabolism is rare.
Their etiology (mechanism) and pathophysiological states (stages) represent dimensions
distinct from each other and both should be used to describe the condition in each
individual patient.
Whatever the underlying etiology, diabetes may develop through various physical conditions
and its pathophysiology may change with the treatment.
Pathophysiological states (stages) of diabetes are to be differentiated into the following
three stages based on the insufficiency of insulin action: ① not requiring insulin
therapy; ② requiring insulin therapy for glycemic control; and ③ requiring insulin
therapy to prevent ketosis and to support/sustain life.
Insulin‐dependent state refers to the life‐threatening status in which patients who
do not receive exogenous insulin are prone to ketosis. In contrast, non‐insulin dependent
state refers to a state in which insulin injection is required not to prevent ketosis
or to support/sustain life but to ameliorate glycemic control. Thus, patients receiving
insulin therapy are not always in an insulin‐dependent state.
2
Goals and Strategies for Diabetes Management
Q2‐1 What are the objectives of diabetes management?
The objectives of diabetes management are to improve metabolic dysfunctions resulting
from hyperglycemia, to prevent the development or progression of diabetic complications
and conditions associated with diabetes, and to enable affected individuals to maintain
their quality of life (QOL) and life expectancy comparable to those of healthy individuals.
Q2‐2 How is a basic diabetes treatment strategy developed for each patient? (Figure
4)
Figure 4
Treatment of patients in a non‐insulin‐dependent state. This provides a guide to the
management of patients without acute metabolic disorder (i.e., those who had a casual
blood glucose level of 250–300 mg/dL [13.9–16.7 mmol/L] or less than 250 to 300 mg/dL
with a negative urinary ketone test). The glycemic goal should be determined individually
depending on the disease condition or age of the patient but is generally set at HbA1c
<7.0%. ‘Diet therapy’ and ‘exercise therapy’ are referred to as ‘medical nutrition
therapy (MNT)’ and ‘physical activity/exercise’, respectively, elsewhere in this guideline.
The treatment strategy for diabetes may vary depending on the type, disease condition,
age, metabolic abnormality, and status of diabetic complications.
Insulin therapy is to be given not only to patients who are insulin‐dependent but
also to pregnant patients, patients undergoing surgery that involves whole‐body management,
and patients with severe infection, even if they are not insulin‐dependent. In addition,
insulin therapy is to be given to those in whom glycemic goals are not achievable
with oral hypoglycemic agents (OHAs) or glucagon‐like peptide 1 (GLP‐1) receptor agonists.
OHA and/or GLP‐1 agonist therapy is to be given to non‐insulin‐dependent patients
in whom favorable glycemic control is not achievable with adequate medical nutrition
therapy (MNT) and physical activity/exercise continued for 2–3 months. OHA and/or
GLP‐1 agonist therapy or insulin therapy may be given to these patients from the outset
depending on the severity of the metabolic disorder involved.
Continued therapy is essential for patients with diabetes to prevent the onset or
progression of complications. Team care‐based diabetes education for these patients
forms the cornerstone of their diabetes treatment.
Q2‐3 How is the glycemic goal set for each individual patient? (Figure 5)
Figure 5
Glycemic control targets. Control targets are established individually, in consideration
of age, duration of disease, organ damage, risk of hypoglycemia, support structures,
etc. *1 When targets can be attained by appropriate MNT or physical activity/exercise,
or during pharmacotherapy without the occurrence of side effects such as hypoglycemia.
*2 From the perspective of preventing complication, HbA1c target value is set at <7%.
A fasting blood glucose level <130 mg/dL (7.2 mmol/L) and a 2‐h postprandial blood
glucose level <180 mg/dL (10.0 mmol/L) can be used as an approximate guideline for
the corresponding blood glucose levels. *3 When intensification of treatment is considered
difficult due to side effects such as hypoglycemia or for other reasons. *4 All target
values are for adults, not including pregnant women.
Glucose levels in affected individuals should be controlled as close to normal as
possible. Achieving and maintaining favorable glycemic control early after initiation
of treatment is likely to lead to favorable long‐term outcomes in these individuals1.
Q2‐4 How is the onset of chronic diabetic complications prevented or their progression
delayed?
Diabetes management is aimed not merely at glycemic control1 but also at ensuring
continued smoking cessation and control of blood pressure and lipid levels, thereby
preventing chronic diabetic complications or delaying their progression2, 3.
3
Medical Nutrition Therapy (MNT)
Q3‐1 What is the role of MNT and the optimal nutritional balance in MNT for patients
with diabetes?
Carbohydrates, proteins and fats should account for 50–60%, ≤20%, and 20–30%, respectively,
of the total energy intake in MNT for patients with diabetes.
The ratios of macronutrients may vary depending on physical activities and the severity
of diabetic complications, as well as on the food preferences of each patient with
diabetes.
CQ3‐2 Is MNT education by registered dieticians effective?
MNT education by registered dieticians is effective1, 2. (Grade A: 100% agreement)
Q3‐3 What is the ideal body weight (IBW) and how is the total energy intake determined
for each patient with diabetes?
The goal of MNT for patients with type 2 diabetes is to optimize their total energy
intake, thereby helping them maintain a favorable metabolic state.
For each patient with type 2 diabetes, the IBW is to be calculated consistent with
a body mass index (BMI) value of 22, and his/her total energy intake is to be calculated
by the following equations:
Total energy intake (kcal/day) = IBW (kg) × physical activity (kcal/kg IBW/day).
IBW (kg) = (height [m])2 × 22.
Physical activity (kcal/kg IBW/day) =
25–30: light physical activity (e.g., jobs mainly involving desk work),
30–35: moderate physical activity (e.g., jobs mainly involving standing work),
>35: heavy physical activity (e.g., jobs mainly involving heavy physical labor).
It is less practical to uniformly aim for the IBW in all patients with type 2 diabetes,
irrespective of their initial BMI values. Rather, given that the body weight reflects
the energy balance, it is advised to aim for a 5% reduction in body weight in obese
individuals with type 2 diabetes; and to aim for the IBW, depending on its possible
improvement of metabolic conditions or its feasibility.
Q3‐4 How does the dietary carbohydrate intake affect diabetes management?
No relationship has been shown between the carbohydrate intake, the risk of diabetes,
and glycemic control.
The consumption of sucrose‐containing sweets and juices is not advised, given that
they may worsen glycemic control and lead to metabolic syndrome.
Patients should limit their intake of fruits up to one unit at a time. ※In Japan,
a common serving size is 80 kcal or a multiple thereof. Thus, 80 kcal is set as 1
unit for discussing amounts of nutrients in MNT.
The effects of artificial sweeteners on glycemic control have not been fully investigated.
Instructions on carbohydrate counting are effective in helping patients on insulin
therapy achieve optimal glycemic control.
Q3‐5 How does the dietary fiber intake affect diabetes management?
Given that dietary fiber has been shown to be effective in improving diabetic states,
patients with diabetes are encouraged to consume ≥20 g of dietary fiber daily, irrespective
of their carbohydrate intake.
No evidence is available to support food choice based on the glycemic index (GI) in
diabetes management.
Q3‐6 How does the dietary protein intake affect diabetes management?
There is no evidence to demonstrate that an increased protein intake is associated
with an increased risk of diabetic nephropathy.
An intake that accounts for ≥20% of the total energy intake may increase the risk
of mortality from any cause including atherosclerosis and the risk of diabetes. No
evidence is available to support the long‐term safety of the practice.
Q3‐7 How does the dietary fat intake affect diabetes management?
While no clear relationship has been shown between the total dietary fat intake and
the risk of diabetes, an increased saturated fatty acid (SFA) intake has been shown
to be associated with the risk of diabetes.
The dietary fat intake should account for 20–30% of the total energy intake (SFA,
≤7%) in patients with diabetes. When it accounts for >25%, care needs to be taken
to modify the fatty acid composition by reducing the SFA intake.
No evidence is available to support the benefits of n‐3 fatty acids in diabetes management.
Q3‐8 How does the dietary vitamin and mineral intake affect diabetes management?
No clear relationship has been shown between the dietary vitamin and mineral intake
and diabetes.
Q3‐9 How does the dietary salt intake affect diabetes management?
Dietary salt restriction has been shown to be useful for reducing the risk of cardiovascular
disease in inadequately controlled diabetes.
Q3‐10 When is the consumption of alcohol allowable in patients with diabetes?
The alcohol intake is to be individualized for each patient with 20–25 g of absolute
ethanol equivalent daily as a measure of the upper limit. At present, the differences
in how different types of alcoholic beverage impact diabetes management remain unclear;
however, attention needs to be paid to carbohydrate‐derived energy in low‐malt beers.
The intake of alcohol may lead to an acute episode of hypoglycemia in patients receiving
sulfonylurea (SU) or insulin therapy, and it therefore needs to be closely monitored.
Biguanides, which are known to cause lactic acidosis, are contraindicated in individuals
whose intake of alcohol is excessive. However, the consumption of alcohol may be allowable,
if it is kept reasonable individuals whose diabetes is well controlled and who are
capable of self‐managing potential problems associated with the intake of alcohol.
4
Physical Activity/Exercise
Q4‐1 Is a medical check‐up required before implementing physical activity/exercise?
Prior to implementing physical activity/exercise in a patient with diabetes, the patient
needs to be evaluated for the presence and severity of cardiovascular disease, peripheral/autonomic
neuropathy, advanced retinopathy, nephropathy, and orthopedic diseases1.
Screening for cardiovascular disease is recommended for asymptomatic patients with
multiple risk factors, those with cerebrovascular or peripheral atherosclerotic disease,
those with electrocardiographic evidence of ischemia, and those undertaking high‐intensity
exercise2.
Q4‐2 Is exercise effective for patients with type 2 diabetes?
Aerobic exercise is associated with improvements in glycemic control3, insulin resistance,
cardiopulmonary function4, and lipid metabolism5, as well as reductions in blood pressure.
(Grade A: 100% agreement)
Both aerobic and resistance exercise are effective for improving glycemic control,
and are even more effective when combined6. (Grade A: 100% agreement)
CQ4‐3 Is exercise effective for patients with type 1 diabetes?
While there is no consensus on the effects of exercise on long‐term glycemic control7,
8, exercise is associated with a reduced risk of cardiovascular disease and improved
quality of life (QOL). (Grade B: 100% agreement)
Q4‐4 What are aerobic and resistance exercise?
Aerobic exercise is defined as exercise involving a sufficient supply of oxygen and
adenosine triphosphate (ATP) resynthesized through reactions between carbohydrates
and lipids as its substrates as energy sources, and continuous rhythmical and repeated
movements of the major skeletal muscles lasting for 10 min or longer. Aerobic exercises
enhance the cardiopulmonary function. Resistance exercises involve skeletal muscle
loading and are performed to enhance the muscular function (muscle strength and endurance).
Q4‐5 How should an exercise regimen be implemented in practice?
It is generally recommended that exercise involving moderate‐intensity aerobic exercise
lasting for 20–60 min each time or a total of ≥150 min per week be implemented on
a daily basis (preferably), or at least 3–5 times a week. It is also recommended that
resistance exercise be implemented 2–3 times a week concurrently with aerobic exercise1.
It is advisable to increase the intensity and amount of exercise in a stepwise fashion
and to include warm‐ups and cool‐downs before and after exercise in daily life. It
is also advisable to examine both feet closely and to use properly fitting cushioned
shoes.
Patients receiving insulin or glucose‐lowering agents (SUs in particular) may experience
episodes of hypoglycemia during exercise, on the day of exercise, or on the day after
exercise. It is therefore recommended that patients receiving insulin adjust the duration,
type and amount of exercise being performed and the doses of drugs being used (as
a rule, a dose reduction of ultra‐fast‐acting insulin before exercise) and to eat
as required before and during exercise through the self‐monitoring of blood glucose
(SMBG). It is especially recommended that patients receiving insulin consume one to
two units of easily absorbed carbohydrates before exercise if their pre‐exercise glucose
level is below 100 mg/dL (5.6 mmol/L)1.
Patients who are in good physical condition may not need to discontinue exercise simply
due to hyperglycemia; however, patients with type 1 diabetes and urine ketone bodies
should refrain from exercise9.
5
Treatment with Glucose‐Lowering Agents (Excluding Insulin)
Q5‐1 What are the indications for glucose‐lowering agents?
Glucose‐lowering agents are indicated for patients with non‐insulin‐dependent stages
of diabetes who fail to achieve favorable glycemic control with adequate MNT and/or
physical activity/exercise of 2–3 months in duration1, 2, 3. However, glucose‐lowering
agents, including insulin, are indicated, along with MNT and/or physical activity/exercise,
for patients in non‐insulin‐dependent stages who require the elimination of glucotoxicity.
The absolute indications for insulin therapy include type 1 diabetes, pregnancy complicated
by diabetes not amenable to control by MNT alone, diabetic coma, severe infection,
surgery requiring whole‐body management In these cases, glucose‐lowering agents are
not indicated and insulin therapy should be initiated immediately.
Q5‐2 How are glucose‐lowering agents chosen for diabetes treatment?
The choice of glucose‐lowering agents should be individualized for each patient according
to the disease condition, with attention also given to their pharmacological and safety
profiles. With informed consent obtained from the patient, the drug(s) should be initiated
at a low dose and gradually titrated upwards as required depending on the glycemic
control of the patient at that time.
Q5‐3 What are the characteristics of sulfonylureas (SUs)?
Sulfonylureas (SUs) potently lower blood glucose level through their ability to promote
the secretion of insulin from pancreatic β cells and current evidence demonstrates
their usefulness in reducing microangiopathy3. SUs have been shown to readily exert
their effects in patients with preserved insulin capacity; however, they have often
been shown to be associated with the side effect of hypoglycemia. SUs are also associated
with weight gain in patients who are less adherent to MNT and/or physical activity/exercise4.
Q5‐4 What are the characteristics of biguanides?
Biguanides are currently used as first‐line glucose‐lowering agents in Western countries.
Biguanides exert their effect by inhibiting hepatic glucose production as well as
by improving peripheral insulin sensitivity. Current evidence demonstrates their usefulness
in reducing macroangiopathy in patients with type 2 diabetes5, 6, 7, 8. Although they
are rarely associated with lactic acidosis, caution needs to be taken to determine
whether the patient can be safely treated with biguanides.
Q5‐5 What are the characteristics of α‐glucosidase inhibitors?
α‐glucosidase inhibitors, which inhibit intestinal glycolysis and delay intestinal
glucose absorption, suppress postprandial hyperglycemia and hyperinsulinemia and should
be taken immediately before meals; they are also often associated with flatus and
diarrhea. Hypoglycemia in patients treated with these agents can be effectively improved
with the ingestion of only glucose.
Q5‐6 What are the characteristics of thiazolidinediones (TZDs)?
Thiazolidinediones (TZDs) improve glycemic control by promoting peripheral insulin
sensitivity and inhibiting hepatic glucose release; they are also often associated
with weight gain due to their ability to promote fluid retention and adipocyte differentiation.
Patients receiving TZDs require monitoring for edema, anemia and fracture associated
with the use of TZDs9, 10, 1, 2, 3.
Q5‐7 What are the characteristics of glinides?
Glinides correct postprandial hyperglycemia by immediately promoting insulin secretion,
with their action diminishing in such a short time that they are less associated with
the risk of hypoglycemia.
Q5‐8 What are the characteristics of DPP‐4 inhibitors?
DPP‐4 inhibitors glucose‐dependently promote postprandial insulin secretion while
at the same time inhibiting glucagon secretion, thus improving both fasting and postprandial
hyperglycemia. While the risk of hypoglycemia with DPP‐4 inhibitor monotherapy is
small, combination therapy with an SU or insulin often increases the risk of hypoglycemia,
suggesting the rationale for reducing the dose of either partnering agent1, 2, 1,
2, 3.
DPP‐4 inhibitors were previously thought to be associated with the risk of acute pancreatitis,
pancreatic cancer or infections; however, current evidence appears to argue against
this4. They are not associated with an increased risk of macroangiopathy5, 6, 7. Thus,
at present, DPP‐4 inhibitors appear to have a favorable safety profile.
Q5‐9 What are the characteristics of GLP‐1 receptor agonists?
GLP‐1 receptor agonists, which are available as injectable agents, promote postprandial
insulin secretion in a glucose‐dependent manner while at the same time inhibiting
glucagon secretion; thus they improve both fasting and postprandial hyperglycemia
and are less associated with a risk of hypoglycemia. While these agents have also
been shown to exert their glucose‐lowering effect in combination with an SU or insulin,
this combination therapy has been shown to be associated with an increased risk of
hypoglycemia, suggesting the rationale for reducing the dose of either partnering
agent8, 9.
GLP‐1 receptor agonists are associated with gastrointestinal symptoms. Thus, to alleviate
the onset of such symptoms, GLP‐1 receptor agonists need to be initiated at a low
dose and titrated upwards as required. Current evidence suggest that these agents
are not associated with a risk of acute pancreatitis1; their cardiovascular safety
has also been demonstrated2.
Q5‐10 What are the characteristics of SGLT2 inhibitors?
SGLT2 inhibitors inhibit glucose reabsorption in the proximal renal tubule and promote
urinary glucose excretion, thus exerting their glucose‐lowering effect; they not only
improve glycemic control independently of insulin‐mediated mechanisms but also associated
with body weight reduction.
Among the SGLT2 inhibitors, empagliflozin has been shown to significantly delay the
onset of cardiovascular events in patients at high risk for these events3.
SGLT2 inhibitors are associated with an increased frequency of urinary tract infections
and genital infections as adverse effects3, 4, 5. Other adverse effects include dehydration
accompanied by symptoms such as thirst, polyuria, pollakiuria, or hypotension, dehydration‐associated
thromboembolism including cerebral infarction, events associated with increased ketone
bodies, and an increased incidence of rash. Their clinical implications require currently
further examination.
Q5‐11 Is combination therapy with glucose‐lowering agents effective?
In patients failing to achieve their glycemic target while on monotherapy with a first‐line
agent, consideration may be given to increasing the dose of the first‐line agent,
switching to a more potent glucose‐lowering agent, or combining the first‐line agent
with another glucose‐lowering agent with a different mechanism of action. No clear
synergistic effect has been demonstrated between agents used in combination, and no
guidelines have been established for combination therapy with glucose‐lowering agents.
In patients with inadequate glycemic control despite monotherapy with an SU or metformin,
combination therapy with another glucose‐lowering agent with a different mechanism
of action is usually considered; combination therapy with such agents has shown to
be effective for lowering glucose levels6, 7, 8, 9, 10, 11, 12. Combination therapy
with three or more agents (other than combinations of an SU and aglinide or a DPP‐4
inhibitor and a GLP‐1 receptor agonist) has been shown to be effective for lowering
glucose levels13, 14, 15, 16, 17.
Q5‐12 How should patients with inadequate glycemic control despite treatment with
glucose‐lowering agents be managed?
In patients with inadequate glycemic control despite combination therapy with glucose‐lowering
agents, consideration needs to be given to reassessing MNT and/or physical activity/exercise
as well as to adding basal insulin therapy or switching to intensive insulin therapy.
6
Insulin Therapy
Q6‐1 What types of insulin formulation are available?
The currently available insulin formulations are classified based on their onset/duration
of action into rapid‐acting insulin, regular insulin, intermediate‐acting (neutral
protamine Hagedorn, NPH) insulin, long‐acting insulin, premixed regular/intermediate‐acting,
premixed rapid‐acting/intermediate‐acting (or biphasic) insulin, and rapid‐acting
and long‐acting insulin combination formulations.
Intermediate‐ or long‐acting insulin formulations are used to supplement basal insulin
secretion, while regular or rapid‐acting insulin formulations are used to supplement
bolus insulin secretion.
Q6‐2 What are the indications for insulin therapy?
Absolute indications for insulin therapy include insulin‐dependent states, including
type 1 diabetes, hyperglycemic coma (diabetic ketoacidosis, hyperglycemic hyperosmolar
syndrome, lactic acidosis), and pregnancy complicated by diabetes that is not adequately
controlled by MNT alone. Insulin therapy is also recommended for serious infections
and surgery requiring systemic management.
Insulin therapy is also implemented in patients with type 2 diabetes having inadequate
glycemic control despite MNT, increased physical activity/exercise and therapy with
non‐insulin glucose‐lowering agents or when hyperglycemia‐associated glucose toxicity
must be eliminated.
Q6‐3 What are the adverse reactions that occur in association with insulin therapy?
Insulin therapy may be associated with hypoglycemia as well as a transient worsening
of retinopathy or neuropathy in some patients1, 2. Patients receiving insulin therapy
need to be monitored for long‐term risks associated with insulin therapy, such as
weight gain3.
Q6‐4 What approaches are available for insulin therapy in type 1 diabetes?
Multiple insulin injection therapy (3–4 injections/day) or continuous subcutaneous
insulin infusion (CSII) are available to optimize glycemic control in type 1 diabetes4.
CQ6‐5 Is intensive insulin therapy effective in suppressing microangiopathy in type
1 diabetes?
Intensive insulin therapy, which combines multiple insulin injections or CSII and
self‐monitoring of blood glucose (SMBG) has been shown to be effective in preventing
the onset of microangiopathy (retinopathy, nephropathy and neuropathy) and in suppressing
their progression5, 6. (Grade A: 100% agreement)
CQ6‐6 Is intensive insulin therapy effective in suppressing macroangiopathy in type
1 diabetes?
Intensive insulin therapy that combines multiple insulin injection therapy and SMBG
has been shown to also be effective in suppressing the progression of macroangiopathy
(coronary artery disease, cerebrovascular disease, and peripheral artery disease)7,
8. (Grade A: 100% agreement)
Q6‐7 What are the indications/approaches for insulin therapy in type 2 diabetes?
Insulin therapy is to be implemented in patients with type 2 diabetes having inadequate
glycemic control despite MNT, increased physical activity/exercise and treatment with
non‐insulin glucose‐lowering agents3, 8, 9, 10.
While once‐daily injection of long‐acting insulin or twice‐daily premixed insulin
(morning and evening) may be sufficient to provide favorable glycemic control in patients
with mild diabetes, intensive insulin therapy with multiple insulin injection is to
be implemented in those with moderate to severe diabetes8, 1, 2.
Combination therapy with insulin and oral glucose‐lowering agents (SUs3, 1, fast‐acting
insulin secretagogues [glinides2, 1, 2, biguanides3, 4, 5, 6, α‐glucosidase inhibitors7,
8, insulin sensitizers9, 1, 2, 3, and], DPP‐4 inhibitors4) or GLP‐1 receptor agonists5
are shown to improve glycemic control and reduce the insulin dose being used in patients
with type 2 diabetes.
CQ6‐8 Is intensive insulin therapy effective in suppressing microangiopathy in type
2 diabetes?
Strict glycemic control with intensive insulin therapy has been shown to be effective
in preventing the onset of microangiopathy (retinopathy, nephropathy, and neuropathy)
as well as in suppressing the progression of microangiopathy8, 9. (Grade A: 100% agreement)
Q6‐9 Is intensive insulin therapy effective in suppressing macroangiopathy in type
2 diabetes?
Intensive insulin therapy has been shown to be effective in preventing the onset of
macroangiopathy in type 2 diabetes9, 6, 7.
7
Diabetes Self‐Management Education and Support for the Self‐management of Diabetes
CQ7‐1 Are organized support and education for the self‐management of diabetes and
support useful for the management of diabetes?
Organized education and support for the self‐management of diabetes and have been
shown to be useful for diabetes management1, 2. (Grade A: 100% agreement)
CQ7‐2 Is group and individualized education useful for the diabetes management?
Both group and individualized education has been shown to be useful for diabetes management3,
4. (Grade A: 85% agreement)
CQ7‐3 Is the self‐monitoring of blood glucose (SMBG) useful for diabetes management?
SMBG has been shown to be useful for patients with type 1 diabetes and for patients
with type 2 diabetes receiving insulin therapy5, 6. (Grade A: 95% agreement)
Q7‐4 What are the psychological issues in diabetes management and treatment?
Diabetes is often associated with depressive symptoms and anxiety disorders specific
to the disease, leading to deficient self‐care, worsening of glycemic control, an
increased risk of diabetic complications, and an impaired QOL, thus adversely affecting
the prognosis of affected patients. Intervention that addresses both depressive symptoms
and diabetes‐related mental distress and anxiety is required to improve the self‐care
abilities and glycemic control of affected patients.
CQ7‐5 Are psychological/behavioral approaches effective in diabetes management?
Psychological/behavioral approaches have been shown to be effective in diabetes management7,
8. (Grade A: 95% agreement)
Q7‐6 Is depression screening/treatment important in diabetes management?
After at‐risk patients with diabetes are screened for depression, systematically coordinated
care for both diabetes and depression is essential9, 10.
Q7‐7 How are the available guidelines and practice manuals to be used in practice?
Practice manuals represent guides for clinicians as to how to translate the treatment
policies defined in the guidelines into daily clinical practice as they are based
on systematic reviews of the available scientific evidence. Healthcare teams and patients
are encouraged to share relevant information and promote decisions that would honor
the needs and preferences of individual patients.
8
Diabetic Retinopathy
CQ8‐1 Is a routine ophthalmologic check‐up useful for preventing the onset/progression
of diabetic retinopathy?
A routine ophthalmologic check‐up has been shown to be useful for preventing the onset/progression
of diabetic retinopathy1, 2, 3, 4. (Grade A: 100% agreement)
CQ8‐2 Is glycemic control useful for the management of diabetic retinopathy?
Glycemic control has been shown to be useful in suppressing the onset/progression
of diabetic retinopathy in patients with type 1 and type 2 diabetes5, 6, 7. (Grade
A: 100% agreement)
CQ8‐3 Is blood pressure control useful for the management of diabetic retinopathy?
Blood pressure control has been shown to be useful for suppressing the onset/progression
of diabetic retinopathy in patients with type 2 diabetes8, 9. (Grade A: 100% agreement)
CQ8‐4 Is lipid control useful for the management of diabetic retinopathy?
Fenofibrates have been shown to have the potential to suppress the progression of
diabetic retinopathy in dyslipidemia complicated by type 2 diabetes7, 10. (Grade B:
100% agreement)
Q8‐5 Are antiplatelet agents useful for preventing the onset/progression of retinopathy?
There is no clinical evidence to suggest the usefulness of antiplatelet agents in
suppressing the onset/progression of diabetic retinopathy.
CQ8‐6 Is ophthalmologic treatment useful for preventing the progression of retinopathy?
Ophthalmologic treatment such as retinal photocoagulation has been shown to be useful
for suppressing the progression of retinopathy1, 2. (Grade A: 100% agreement)
Q8‐7 Is pregnancy with pre‐existing diabetes a risk factor for the onset/progression
of diabetic retinopathy?
Pregnancy with pre‐existing diabetes has been shown to promote the onset/progression
of diabetic retinopathy3, 1, 2.
Q8‐8 Is diabetic retinopathy a risk factor for the onset of other diabetes‐associated
complications?
Diabetic retinopathy is a risk factor for diabetic nephropathy and macroangiopathy1,
2, 3, 4, 5.
9
Diabetic Nephropathy
CQ9‐1 Is the measurement of urinary albumin useful for the early diagnosis of diabetic
nephropathy?
The measurement of urinary albumin has been shown to be useful in the early diagnosis
of diabetic nephropathy1. (Grade A: 100% agreement)
Q9‐2 What parameters are used to assess the renal function?
The renal function is to be evaluated as the estimated glomerular filtration rate
(eGFR) from the serum creatinine (Scr) concentration, as determined by an enzymatic
method2.
Insulin clearance (Ic) or creatinine clearance (Ccr) allows the renal function to
be more accurately assessed than the eGFR.
Estimated glomerular filtration rate (eGFR)
The eGFR is easily assessed as an index of the renal function, rather than Ccr or
insulin clearance (Cin). The eGFR is calculated by the following equation for Japanese
adults based on the Scr concentration2:
eGFR
(
mL
/
min
/
1.73
m
2
)
=
194
×
Scr
(
mg/dL
)
−
1.094
×
Age
−
0.287
(
×
0.789
,
if female
)
.
The accuracy rate of this equation (within 30% of the measured GFR) is 75%. The eGRF
may be overestimated in subjects with reduced muscle mass.
Alternatively, the eGFR can be calculated by the following equation based on the serum
cystatin C (Cys‐C) concentration5:
eGFRcys‐c (mL/min
/
1.73
m
2
)
=
104
×
Cys‐C
−
1.019
×
0
.
996
Age
(
×
0.996
,
if female
)
−
8
.
The serum Cys‐C concentration is influenced by muscle mass or diet (or nutritional
conditions).
CQ9‐3 Is glycemic control effective for the management of diabetic nephropathy?
Glycemic control has been shown to be effective for suppressing the progression of
nephropathy in patients with early‐stage diabetic nephropathy4, 5. (Grade A: 90% agreement)
Glycemic control has been shown to have the potential to suppress the progression
of nephropathy in patients with overt diabetic nephropathy6. (Grade B: 90% agreement)
CQ9‐4 Is blood pressure control effective for the management of diabetic nephropathy?
Blood pressure control has been shown to be effective for the management of diabetic
nephropathy in all stages7, 8, 9. (Grade A: 95% agreement)
CQ9‐5 Is lipid control effective for the management of diabetic nephropathy?
Lipid control has been shown to be effective for suppressing the progression of diabetic
nephropathy in patients without renal impairment10, 1. (Grade B: 95% agreement)
CQ9‐6 Are angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor
antagonists (ARBs) recommended as first‐line medications for blood pressure control
in patients with diabetic nephropathy?
Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists
(ARB) are recommended as first‐line medications for blood pressure control in patients
with diabetic nephropathy2, 3. (Grade A: 100% agreement)
CQ9‐7 Is dietary salt restriction recommended for the management of diabetic nephropathy?
Dietary salt restriction is recommended for the management of diabetic nephropathy1,
2. (Grade A: 95% agreement)
Q9‐8 Is dietary protein restriction effective for the management of diabetic nephropathy?
Dietary protein restriction may potentially be effective for the management of diabetic
nephropathy1, 2.
Q9‐9 Is the treatment of anemia effective for suppressing the progression of diabetic
nephropathy?
It remains unclear if the treatment of anemia may have a role in suppressing the progression
of diabetic nephropathy3.
Q9‐10 Is diabetic nephropathy a risk factor for other complications in diabetic patients?
Diabetic nephropathy frequently occurs concomitantly with cardiovascular disease.
Patients with diabetic nephropathy show a high rate of cardiovascular disease‐related
mortality.
A decreased GFR and the occurrence of albuminuria are independent risk factors for
cardiovascular disease4.
10
Diabetic Neuropathy
Q10‐1 How is diabetic neuropathy diagnosed? (Table 4)
Table 4
The diagnostic criteria for distal symmetric polyneuropathy proposed by the Diabetic
Neuropathy Study Group, Japan (the original version was published in 2004; the revised
version was published in 2005)
Prerequisite condition (Must meet the following two items)
1. Diagnosed as diabetes
2. Other neuropathies than diabetic neuropathy can be excluded
Criteria (Meet any two of following three items)
1. Presence of symptoms considered to be due to diabetic polyneuropathy
2. Decrease or disappearance of bilateral ankle reflex
3. Decreased vibration in bilateral medial malleoli
Diabetic neuropathy has no specific symptoms or assessments and no global consensus
has been reached on its diagnostic criteria. Thus, while a comprehensive assessment
is required to establish its diagnosis based on neurological symptoms and laboratory
test results, the validity of the criteria proposed by the Japanese Study Group of
Diabetic Nephropathy2, 3 is thought to be high enough for routine clinical use.
John Wiley & Sons, Ltd
Diabetic neuropathy represents one of the most common complications in patients with
diabetes. It is therefore preferable that patients with diabetes undergoing physical
examinations be examined for the presence or absence of diabetic neuropathy; if present,
its clinical stage determined.
In diagnosing diabetic neuropathy, patients are to be not only interviewed about neurological
symptoms but also to be examined for sensations such as pain sensation (with a toothpick/bamboo
skewer), vibration sensation (with a C128 tuning fork), pressure sensation (with a
monofilament) as well as for Achilles’ tendon reflex; the assessment can be as comprehensive
as possible. Other findings, such as dry feet, cracked feet, foot calluses or ulcers,
may suggest the presence of neuropathy and prove helpful in establishing the diagnosis.
Heart rate variability (HRV) testing is a convenient and useful test to assess the
autonomic nerve function.
Nerve conduction examinations are essential for the definitive diagnosis of diabetic
neuropathy and are useful in the diagnosis of asymptomatic neuropathy.
Q10‐2 How is diabetic neuropathy classified?
Diabetic neuropathy is divided into distal symmetric polyneuropathy and focal mononeuropathy1,
2.
Q10‐3 What are the risk factors for the onset/progression of diabetic neuropathy?
The risk factors for the onset/progression of diabetic neuropathy include: ① poor
glycemic control, ② duration of diabetes, ③ hypertension, ④ dyslipidemia, ⑤ smoking,
and ⑥ drinking3. Among these, poor glycemic control is the most prominent risk factor;
indeed, the incidence of neuropathy in patients with poor glycemic control has been
shown to be high.
CQ10‐4 Is glycemic control effective for the management of diabetic neuropathy?
Strict glycemic control has been shown to suppress the onset/progression of diabetic
neuropathy4, 5. (Grade A: 95% agreement)
Q10‐5 How is pharmacotherapy to be implemented in patients with neurosensory damage?
Neurosensory damage often resolves with improved glycemic control and lifestyle modification
in patients with mild painful neuropathy. Non‐steroidal anti‐inflammatory drugs (NSAIDs)
have only been shown to be effective in mild cases.
Tricyclic antidepressants6, pregabalin7, 8, and duloxetine9, 10 are recommended as
first‐line medications for patients with moderate to severe painful neuropathy.
Epalrestat has been shown to suppress the progression of diabetic neuropathy in some
patients.
Q10‐6 How is autonomic nerve damage treated?
Neurosensory damage often improves with improved glycemic control and lifestyle modification
in patients with mild autonomic neuropathy. However, symptom‐specific pharmacotherapy
is required for patients whose activities of daily living (ADL) are impaired in association
with advanced neuropathy.
Q10‐7 How is mononeuropathy treated ?
Mononeuropathy has been shown to often resolve spontaneously, independent of glycemic
control.
Q10‐8 Is diabetic neuropathy a risk factor for other complications in diabetic patients?
Diabetic neuropathy has been shown to be a risk factor for diabetic retinopathy and
nephropathy1.
11
Diabetic Foot
Q11‐1 What is diabetic foot?
Diabetic foot is globally defined as ‘infections, ulcers and destructive lesions occurring
on the lower limb tissue of patients with diabetes in association with ongoing neuropathy
and peripheral artery disease’.
Diabetic foot occurs in response to external factors in the presence of hypoesthesia
due to neuropathy, foot deformities, dry or keratinized skin, and decreased blood
flow due to peripheral artery disease. When diabetic foot is complicated by infection,
it is likely to become severe, leading not only to lower limb amputation but also
to a worse prognosis1, 2.
CQ11‐2 Is a routine foot examination effective for the prevention of diabetic foot?
While there is a paucity of evidence to support the effectiveness of routine foot
examinations in the prevention of diabetic foot, the incidence of lower limb amputations
has been observed to decrease following the introduction of foot care, including foot
examinations, in clinical practice3. Foot examinations are essential for the early
detection of diabetic foot and the implementation of foot care and are thus thought
to be effective for the prevention of diabetic foot. (Grade A: 85% agreement)
CQ11‐3 Is foot care education effective for the prevention of diabetic foot?
Foot care education is thought to promote the acquisition of relevant knowledge and
improve self‐care activities and is thus thought likely to be effective for achieving
the long‐term prevention of diabetic foot1, 4. (Grade A: 90% agreement)
CQ11‐4 Is glycemic control effective for preventing diabetic foot or lower limb amputations?
To date, very few studies have investigated the effects of intervention with regard
to glycemic control on diabetic foot or amputations5; however, glycemic control is
recommended for the prevention of neuropathy and macroangiopathy, which are risk factors
for diabetic foot. (Grade B by consensus: 100% agreement)
CQ11‐5 Is foot care effective for the prevention of foot ulcers or limb salvage in
high‐risk patients?
While very few studies have shown direct evidence to support the effectiveness of
foot care in the prevention of foot ulcers or lower limb amputations in high‐risk
patients, multidisciplinary collaboration on foot care has been shown to reduce the
incidence of major amputations6. (Grade A: 100% agreement)
Q11‐6 How are foot ulcers treated?
The treatment of diabetic foot in patients with diabetes entails a wide array of interventions,
which include control of their general condition, local procedures (i.e., debridement),
the treatment of infectious disease, revascularization for severe lower limb ischemia,
the use of non‐weight‐bearing/off‐loading devices and specially prepared shoes, walking
rehabilitation, nutritional education, and care support, in which multidisciplinary
team‐based care involving diverse specialists and practitioners remains the cornerstone1.
Infections, abscesses or necrotizing fasciitis associated with the presence of gas
in the deep tissues are indications for emergency surgery. While no established criteria
are available with regard to for indications for amputation, the blood flow of the
prospective amputation site must be evaluated prior to amputation7, 8.
CQ11‐7 Is team‐based care effective in preventing diabetic foot and treating foot
ulcers?
Multidisciplinary team‐based care is reported to improve the outcomes of foot ulcer
treatment9. While there is no direct evidence to show that multidisciplinary team‐based
care prevents diabetic foot ulcers, the incidence of foot amputations has decreased
over time since the establishment of multidisciplinary team‐based care, suggesting
that multidisciplinary team‐based care is effective in preventing foot lesions10.
(Grade A: 100% agreement)
CQ11‐8 Is foot ulcer treatment effective in maintaining the quality of life (QOL)
of affected patients?
Foot ulcer treatment has been shown to be effective in maintaining the QOL of affected
patients1, 2. (Grade A: 100% agreement)
Q11‐9 Is diabetic foot a risk factor for other complications in patients with diabetes?
Diabetic foot is significantly associated with the onset of cardiovascular disease,
higher overall mortality and the onset of depression, suggesting that diabetic foot
represents a risk factor for mortality, cardiovascular disease and depression3, 1.
12
Diabetic Macroangiopathy
Q12‐1 When and how is risk management to be initiated for the prevention of diabetic
macroangiopathy?
It is recommended that the established risk factors for diabetic macroangiopathy (i.e.,
impaired glucose tolerance [IGT], hypertension, dyslipidemia, obesity, and chronic
kidney disease [CKD]), be detected and managed at an early stage1.
Q12‐2 In which diabetic patients is risk management likely to be beneficial in preventing
diabetic macroangiopathy?
All patients with diabetes may be deemed candidates for risk management. However,
tight pharmacological blood pressure and glucose control may be adversely associated
with an increased risk of events in older patients or those with advanced vascular
complications2.
CQ12‐3 Are the modification of lifestyle habits and the correction of obesity effective
in preventing diabetic macroangiopathy?
Conditions, such as IGT, hypertension, dyslipidemia, obesity, and CKD, and lifestyle
habits, such as physical inactivity, an excessive salt intake, and smoking, all represent
risk factors for cardiovascular events. The modification of lifestyle habits and the
correction of obesity are recommended, given that they are shown to be associated
with the amelioration of these risk factors3. (Grade A: 95% agreement)
CQ12‐4 Is glycemic control effective against diabetic macroangiopathy?
Tight glycemic control, initiated early after the onset of diabetes, has been shown
to be effective in suppressing the risk of diabetic macroangiopathy4. (Grade A: 100%
agreement)
CQ12‐5 Is blood pressure control effective in preventing diabetic macroangiopathy?
Tight blood pressure control has been shown to be effective in suppressing the risk
of diabetic macroangiopathy5. (Grade A: 100% agreement)
CQ12‐6 Is lipid control effective in preventing diabetic macroangiopathy?
Lipid control has been shown to be effective in the primary and secondary prevention
of diabetic macroangiopathy6, 7. (Grade A: 100% agreement)
CQ12‐7 Are antiplatelet agents effective in preventing diabetic macroangiopathy?
The use of antiplatelet agents has been shown to be effective in the secondary prevention
of diabetic macroangiopathy8. (Grade A: 100% agreement)
The use of antiplatelet agents is not recommended for the primary prevention of diabetic
macroangiopathy in patients with diabetes9. (Grade A: 90% agreement)
Q12‐8 Is diabetic macroangiopathy a risk factor for other complications in diabetic
patients?
Hyperglycemia represents a common risk factor for diabetic retinopathy, nephropathy,
neuropathy, and macroangiopathy, thus suggesting a relationship between these conditions.
However, at present, there is no clear evidence to demonstrate any direct relationship.
13
Diabetes and Periodontitis
Q13‐1 What is periodontal disease?
Periodontal disease is an inflammatory disease involving plaque bacteria and is broadly
classified into gingivitis, in which inflammation is confined to the gingiva, and
periodontitis, which involves a loss of supporting tissue.
Periodontal disease is a disease of the oral cavity that is reported to affect approximately
80% of the Japanese individuals of middle age or older and is the foremost cause of
dental extraction.
The treatment of periodontal disease entails not only establishing plaque control
in affected patients but also improving inflammation through plaque and calculus removal
from periodontal pockets and ensuring routine post‐removal periodontal maintenance
care aimed at preventing a relapse of the disease.
Q13‐2 Does diabetes influence the onset/progression of periodontal disease?
Periodontal disease has been shown to occur more frequently among patients with type
1 diabetes in comparison to young healthy individuals1.
The risk of the onset of periodontal disease and the progression of alveolar bone
resorption is significantly increased in patients with type 2 diabetes and an HbA1c
value of ≥6.5%2.
CQ13‐3 Is diabetes treatment effective in improving periodontal disease?
Diabetes treatment may lead to the improvement of periodontal tissue inflammation3.
(Grade B: 100% agreement)
Q13‐4 Does periodontal disease affect glycemic control?
Periodontal disease as an inflammatory disease has been epidemiologically shown to
adversely affect glycemic control4.
As periodontal disease becomes more severe, it becomes more difficult to achieve glycemic
control in affected patients5.
CQ13‐5 Is treating periodontal disease effective in improving glycemic control?
The treatment of periodontal disease has been shown to lead to improvement in the
glycemic status of some patients with type 2 diabetes6. (Grade B: 95% agreement)
14
Diabetes Complicated by Obesity (Including Metabolic Syndrome)
Q14‐1 What are the causes of obesity?
Obesity is classified into secondary obesity (i.e., obesity with clear underlying
causes), and primary obesity (i.e., obesity with no clear causes but which is associated
with lifestyle habits such as physical inactivity)1.
While primary obesity is most frequent of all forms of obesity, secondary obesity
includes endocrinologically‐induced obesity, inherited obesity, hypothalamic obesity
and drug induced obesity1.
Q14‐2 How is obesity diagnosed?
In Japan, obesity is defined by a body mass index (BMI) of ≥25 kg/m2 or higher according
to the Japan Society for the Study of Obesity; however, obesity should not to be handled
as a disease in patients without health problems1.
Obesity should be handled as a disease in patients with obesity‐induced or obesity‐associated
health problems, or in patients who are likely to have obesity‐associated health problems
and for whom weight loss is medically indicated1.
Obesity as a disease includes ① obesity‐induced or obesity‐associated conditions requiring
weight reduction for health problems (that are likely to be improved or prevented
with a certain level of weight loss); and ② visceral fat‐associated obesity (visceral
fat area ≥100 cm2 at the umbilical level measured by CT in patients who are currently
free of, but who are likely to develop health problems such as diabetes (defined as
high‐risk obesity requiring intervention with lifestyle modification)1.
Q14‐3 How is obesity‐associated diabetes to be managed?
Secondary obesity is to be carefully ruled out in patients with type 2 diabetes and
obesity, and those who are thought to be likely to have primary obesity are to be
interviewed about their living environmental and psychological factors. Attention
is to be paid to the discontinuation or modification of any lifestyle habits that
cause obesity2. This is to entail, first, instructing patients on lifestyle modification
including MNT and/or physical activity/exercise, stress management and a regular lifestyle
to lose weight2. Pharmacotherapy is to be considered for patients whose glycemic control
is inadequate despite maintaining lifestyle modifications over a certain period2.
Left untreated, obesity often becomes more severe in diabetic patients and obese patients
receiving therapy for hyperglycemia alone3. Attention needs to be focused on ensuring
that these patients proactively modify their lifestyles to achieve favorable glycemic
control without weight gain3.
Q14‐4 Is behavioral therapy effective in reducing body weight and achieving glycemic
control in patients with type 2 diabetes and obesity?
Behavioral therapy needs to be combined with lifestyle modification in order to achieve
and maintain weight reduction over the long term in patients with type 2 diabetes
and obesity4. Obesity is associated with abnormal eating behavior such as speed eating
characterized, by an excessive intake of energy over a short time, and impulse eating,
and eating between meals from post‐lunch to nighttime can be problematic in many of
these patients. Thus, when their treatment goals have been determined, these patients
must be monitored and their overeating behavior should be evaluated through diet journals
and body weight measurements to establish improvements in their eating behavior. Behavioral
enhancement, such as through the implementation of routine motivation measures, is
thought to be effective in maintaining desired behavioral changes. However, there
is currently no clear evidence to support the effectiveness of behavioral therapy
in the achievement of glycemic control in patients with type 2 diabetes and obesity.
Q14‐5 Is pharmacotherapy effective for achieving glycemic control in patients with
type 2 diabetes and obesity?
The use of insulin or SUs is to be minimized in patients with type 2 diabetes and
obesity, given that their uncritical use may promote obesity3.
Medications associated with weight gain include (in addition to insulin and SUs) rapid‐acting
insulin secretagogues (glinides), thiazolidinediones (TZDs), tricyclic antidepressants
(amitriptyline), and atypical antipsychotic agents (olanzapine). The use of these
drugs by patients with type 2 diabetes and obesity warrants caution3.
The appetite‐inhibitory and weight‐reducing properties of glucagon‐like peptide 1
(GLP‐1) receptor agonists may improve glycemic control in patients with type 2 diabetes
and obesity3. Indeed, some GLP‐1 receptor agonists are currently being used to treat
obesity overseas.
CQ14‐6 Is surgical therapy effective for patients with type 2 diabetes and high‐degree
obesity?
The role of obesity surgery has drawn attention. Obesity surgery includes not only
bariatric surgery for high‐degree obesity, but also metabolic surgery, which improves
diabetes or prevents the onset/progression of the disease. Thus, obesity surgery is
an effective treatment option for patients with type 2 diabetes and obesity who are
less amenable to weight reduction5. (Grade B: 100% agreement)
Q14‐7 What is metabolic syndrome?
Metabolic syndrome is defined as a condition that involves any two of the following
conditions, in addition to visceral fat accumulation (visceral fat area ≥100 m2 on
CT measurement at the level of the umbilicus): fasting hyperglycemia (≥110 mg/dL (6.1
mmol/L), dyslipidemia such as hypertriglyceridemia (≥150 mg/dL), hypo‐high‐density‐lipoprotein
(HDL)‐cholesterolemia (<40 mg/dL), and high blood pressure (≥130/85 mmHg)6.
15
Hypertension Associated with Diabetes
Q15‐1 Is hypertension a risk factor for macroangiopathy in patients with diabetes?
Both diabetes and hypertension are established risk factors for atherosclerosis‐associated
macroangiopathy; furthermore, patients with diabetes and hypertension have a higher
incidence of macroangiopathy and a poorer prognosis1.
Q15‐2 Is hypertension a risk factor for microangiopathy in patients with diabetes?
Hypertension in patients with diabetes represents a risk factor for microangiopathy,
such as diabetic nephropathy, retinopathy and neuropathy2.
The correction of hypertension potentially prevents the progression of diabetic nephropathy
in patients with diabetes3.
Angiotensin II receptor antagonists (ARBs) and angiotensin‐converting enzyme (ACE)
inhibitors potentially prevent the progression of microangiopathy3, 4.
Q15‐3 What is the office blood pressure threshold for initiating antihypertensive
therapy in patients with diabetes? (Figure 6)
Figure 6
The treatment of hypertension complicating diabetes mellitus. Excerpt from: The Japanese
Society of Hypertension, Guidelines for the Treatment of Hypertension, 2014, p. 78.
*Care needs to be taken to closely monitor patients with coronary atherosclerosis,
peripheral arterial disease, or older patients with diabetes, for decreased organ
blood flow.
The initiation antihypertensive therapy is deemed to be appropriate for patients with
an office blood pressure of ≥130/80 mmHg.
Intervention with antihypertensive agents are to be immediately initiated for patients
with an office blood pressure of ≥140/90 mmHg.
Lifestyle modification (lasting no more than 3 months) may be indicated for patients
with diabetes and an office blood pressure of 130–139/80–89 mmHg if such modification
is expected to achieve the patient's blood pressure goal; however, antihypertensive
agents are to be initiated immediately when such modification is considered to be
unlikely to achieve the blood pressure goal.
Home blood pressure measurement is strongly recommended and home blood pressure measurement
should be performed prior to office blood pressure measurement when there is discrepancy
between the home and office blood pressure readings.
A home blood pressure of ≥125/75 mmHg is deemed to be an appropriate level for initiating
intervention in patients with diabetes. (Consensus between the Japanese Society of
Hypertension and the Japan Diabetes Society)
CQ15‐4 Is controlling office blood pressure to <130/80 mmHg effective in preventing
the onset of complications in patients with diabetes and hypertension?
A blood pressure of <130/80 mmHg deemed to be appropriate as the office blood pressure
goal for preventing complications in patients with diabetes and hypertension5, 6.
(Grade B: 90% agreement)
While controlling blood pressure to the blood pressure goal is effective in preventing
diabetic complications, particularly cerebrovascular disease, sufficient attention
should be paid to the potential for organ hypoperfusion in association with decreased
blood pressure in patients with diabetes and atherosclerotic coronary disease or peripheral
artery disease, or in older patients with diabetes7, 8. (Grade B: 100% agreement)
(Consensus between the Japanese Society of Hypertension and the Japan Diabetes Society)
CQ15‐5 Are angiotensin‐converting enzyme (ACE) inhibitors or angiotensin II receptor
antagonists (ARBs) used as first‐line antihypertensive medications for patients with
diabetes and hypertension?
ACE inhibitors or ARBs are to be used as first‐line antihypertensive drugs in patients
with diabetes and hypertension, given their organ‐protective and insulin‐sensitizing
properties9, 10. (Grade A: 100% agreement) (Consensus between the Japanese Society
of Hypertension and the Japan Diabetes Society)
Q15‐6 Which is preferable, a calcium channel blocker (CCB) or a diuretic, as an add‐on
agent in patients with diabetes and hypertension
A calcium channel blocker or a low‐dose thiazide diuretic is to be added or combination
therapy with three agents is to be implemented when treating diabetic patients whose
blood pressure is less well controlled with an ACE inhibitor/ARB.
(Consensus between the Japanese Society of Hypertension and the Japan Diabetes Society)
16
Dyslipidemia Associated with Diabetes
Q16‐1 Is dyslipidemia a risk factor for macroangiopathy in diabetes?
Dyslipidemia is a risk factor for macroangiopathy1.
Hyper‐low‐density‐lipoprotein (LDL)‐cholesterolemia is a strong risk factor for coronary
artery disease2.
Q16‐2 Is dyslipidemia a risk factor for microangiopathy in diabetes?
Hypertriglyceridemia is a risk factor for microangiopathy3.
Hypo‐high‐density‐lipoprotein (HDL)‐cholesterolemia is a risk factor for microangiopathy4.
Q16‐3 What are the threshold for initiating antidyslipidemic therapy and its control
goals in diabetes? (Table 5)
Table 5
The lipid control target values in patients with diabetes
Coronary artery disease
Lipid control target values (mg/dL)
LDL‐C
HDL‐C
TG
Non‐HDL‐C
Present
<120
≥40
<150
<150
Absent
<100
<130
Edited by Japan Atherosclerosis Society: Guidelines for Prevention of Atherosclerotic
Cardiovascular Diseases, published 2012,P.42.
John Wiley & Sons, Ltd
The primary goal of antidyslipidemic therapy is to control the LDL‐cholesterol level
to: <100 mg/dL in patients with a history of coronary artery disease and to <120 mg/dL
in patients without a history of coronary artery disease.
The control goal for fasting triglyceride (TG) is <150 mg/dL.
The control goal for HDL‐cholesterol is ≥40 mg/dL.
CQ16‐4 Is MNT effective against dyslipidemia in patients with diabetes?
MNT has been shown to be effective against dyslipidemia in patients with diabetes5.
(Grade A: 100% agreement)
The intake of polyunsaturated fatty acids (PUFA) is recommended6. (Grade A: 100% agreement)
CQ16‐5 Is physical activity/exercise effective against dyslipidemia in patients with
diabetes?
Physical activity/exercise has been shown to be effective against dyslipidemia in
patients with diabetes7. (Grade A: 100% agreement)
CQ16‐6 Is statin therapy effective in reducing the risk of cardiovascular disease
(CVD) or mortality in patients with diabetes and dyslipidemia?
The use of statins has been shown to reduce the risk of CVD and mortality in patients
with diabetes and dyslipidemia8. (Level of recommendation: A [100% consensus])
Statins are the drugs of choice for hyper‐LDL‐cholesterolemia in patients with diabetes9.
(Grade A: 100% agreement)
CQ16‐7 Is the use of non‐statin drugs effective in reducing the risk of CVD or mortality
in patients with diabetes and dyslipidemia?
The use of fibrates has been shown to reduce the risk of non‐fatal CVD in patients
with diabetes and dyslipidemia10. (Grade B: 100% agreement)
The use of fibrates is to be considered for patients with diabetes and hypertriglyceridemia1.
(Grade B: 100% agreement)
17
Impaired Glucose Metabolism in Pregnancy
CQ17‐1 Does glycemic control before and during pregnancy lead to improvements in the
maternal and neonatal prognosis?
While poor glycemic control before and during early‐phase pregnancy has been shown
to be associated with an increased incidence of congenital anomalies and fetal death,
strict glycemic control from well before pregnancy has been shown to be associated
with a reduced incidence of these complications1. (Grade A: 95% agreement)
While poor glycemic control during pregnancy has been shown to be associated with
an increased risk of perinatal complications, including fetal macrosomia, strict glycemic
control during pregnancy has been shown to be associated with a reduction in the risk
of these complications2. (Grade A: 100% agreement)
Q17‐2 How are hyperglycemic disorders diagnosed in pregnancy? (Table 6)
Table 6
Gestational diabetes mellitus: Its definition and diagnostic criteria
Definition
Gestational diabetes mellitus is defined as a state of pre‐diabetic impaired glucose
tolerance which is identified or which occurs for the first time during pregnancy
and which does not include overt diabetes in pregnancy or pregnancy complicated by
diabetes (pre‐gestational diabetes mellitus).
Diagnostic criteria
Gestational diabetes mellitus
Individuals are to be diagnosed with gestational diabetes mellitus if they meet any
of the following criteria in a 75 g oral glucose tolerance test (OGTT):
① Fasting glucose value: ≥92 mg/dL (5.1 mmol/L)
② 1‐h post‐OGTT glucose value: ≥180 mg/dL (10.0 mmol/L)
③ 2‐h post‐OGTT glucose value: ≥153 mg/dL (8.5 mmol/L)
Overt diabetes in pregnancya
Individuals are to be diagnosed with overt diabetes in pregnancy if they meet either
of the following during pregnancy:
① Fasting glucose: ≥126 mg/dL (7.0 mmol/L)
② HbA1c: ≥6.5%
* Individuals with casual glucose values of ≥200 mg/dL (11.1 mmol/L) or 2‐h post‐75
g OGTT glucose values of ≥200 mg/dL (11.1 mmol/L) in pregnancy are to be examined
to see if they meet either ① or ② with the potential diagnosis of overt diabetes in
pregnancy in mind.b
Pre‐gestational diabetes mellitus
Individuals are to be diagnosed with pre‐gestational diabetes mellitus if they meet
either of the following:
① Diabetes mellitus diagnosed before pregnancy
② Pregnancy associated with unequivocal evidence of diabetic retinopathy
a
Overt diabetes mellitus in pregnancy includes diabetes mellitus overlooked before
pregnancy, impaired glucose tolerance resulting from changes in glucose metabolism
during pregnancy and type 1 diabetes mellitus occurring during pregnancy. In either
case, the diagnosis needs to be confirmed in affected individuals after delivery.
b
Individuals are expected to show higher post‐OGTT glucose values during pregnancy
than usual, reflecting increased physiological insulin resistance during pregnancy,
particularly in later stage. Thus, the casual glucose and post‐75 g OGTT values defined
in the diagnostic criteria for diabetes mellitus during non‐pregnancy are not readily
applicable (adapted from1).
John Wiley & Sons, Ltd
Hyperglycemic disorders in pregnancy include ① gestational diabetes mellitus (GDM),
② overt diabetes in pregnancy, and ③ pre‐gestational diabetes mellitus, and are diagnosed
based on 75 g oral glucose tolerance tests (OGTTs), HbA1c values and the clinical
findings3.
Q17‐3 How should patients with diabetes be managed and treated before pregnancy?
Patients with diabetes who wish to become pregnant are to be fully informed about
the importance of strict glycemic control being implemented from well before pregnancy
to prevent congenital anomalies, fetal death and miscarriage due to poor glycemic
control1.
Every effort should be made to achieve glycemic control that is as close to normal
as possible while at the same time avoiding hypoglycemia in these patients1.
Given that oral glucose‐lowering agents are not recommended in patients who wish to
become pregnant, insulin therapy is to be implemented if glycemic control is deemed
inadequate despite MNT1.
All patients with diabetes who wish to become pregnant are to be evaluated for diabetic
complications. If complications are present, they should be managed from well before
pregnancy, as they have been shown to adversely affect the maternal prognosis and
pregnancy outcomes4.
Careful family planning is to be recommended for patients who wish to become pregnant
and the patient is to be fully informed about the potential need for contraception,
to avoid congenital anomalies and miscarriage and in order to ensure healthy neonatal
development and a favorable long‐term maternal prognosis1.
All patients with diabetes who wish to become pregnant are to be evaluated for their
use of antihypertensive and lipid‐lowering agents; these agents are to be reconsidered
in view of pregnancy.
Q17‐4 How should diabetic retinopathy be managed and treated before and during pregnancy?
Diabetic retinopathy has been shown to worsen during pregnancy and after delivery.
Thus, those who wish to become pregnant should be evaluated for glycemic control and
diabetic retinopathy. If present, diabetic retinopathy is to be managed from well
before pregnancy. Given that pre‐proliferative/proliferative retinopathy is more likely
to worsen, patients with either form of retinopathy are to be instructed to attempt
to conceive only after their disease has become stable with ophthalmologic treatment5.
Q17‐5 How should diabetic nephropathy be managed and treated before and during pregnancy?
Diabetic nephropathy during pregnancy has been shown to lead not only to the onset
of pregnancy‐induced hypertension, premature delivery, and renal dysfunction in mothers,
but also to growth retardation in their infants. Thus, the condition represents a
high risk for both the mother and baby4.
When a patient indicates a wish to become pregnant, their renal function is to be
evaluated based on urinary albumin/protein, the glomerular filtration rate (GFR),
and creatinine clearance (Ccr), from well before pregnancy6.
Given that pregnancy has been shown to be associated with a further worsening of the
renal function—likely leading to poor perinatal prognosis in patients with renal impairment—patients
with renal impairment are to be fully informed about these risks before pregnancy
and those who become pregnant are to be given careful counselling as to whether to
continue pregnancy6.
Q17‐6 How pregnant women are screened for gestational diabetes mellitus (GDM)?
Given that screening for gestational diabetes mellitus (GDM), based on risk factors,
such as a family history of diabetes, obesity, a history of fetal macrosomia and age,
is thought likely to lead to many patients with GDM being missed, it is preferable
that all pregnant women be consistently screened for GDM, based on a glucose‐based
assessment including casual and fasting glucose measurements and a glucose challenge
test (GCT); ideally, at first consultation and at between 24 and 28 weeks of gestation7.
Q17‐7 How should glycemic control be implemented in cases involving hyperglycemic
disorders during pregnancy
Glycemic control in pregnant women with hyperglycemic disorders is intended to control
their glucose to as close to that of a healthy pregnant woman as possible, while minimizing
the incidence of hypoglycemia; the target fasting glucose level is 70–100 mg/dL (3.9–5.6
mmol/L) and the target postprandial 2‐h level is <120 mg/dL (6.7 mmol/L).
MNT in pregnant women with hyperglycemic disorders involves not only providing necessary
and sufficient nutrition for healthy fetal development but also ensuring strict glycemic
control and appropriate weight gain8.
Insulin therapy is to be implemented if patient's glycemic control goal is not achievable
with MNT. Intensive insulin therapy, which involves self‐monitoring of blood glucose
(SMBG), is to be employed to better ensure sustained glycemic control9.
While there is a paucity of evidence to support the usefulness of increased physical
activity/exercise in the management of hyperglycemic disorders in pregnancy, increased
physical activity/exercise may have a role to play in promoting health including improving
maternal glycemic control, suppressing excessive weight gain, and providing a change
of pace.
Q17‐8 How should delivery be managed in pregnant women with impaired glucose metabolism?
While vaginal delivery represents the standard approach in women with hyperglycemic
disorders as in healthy pregnancy, the approach should be individualized, with consideration
given to fetal growth and well‐being.
Given that maternal hyperglycemia is a risk factor for neonatal hypoglycemia, the
maternal glucose level at delivery is to be maintained at ≤100 mg/dL (5.6 mmol/L)
in pregnant patients with hyperglycemic disorders.
Q17‐9 How should patients with gestational diabetes mellitus (GDM) or overt diabetes
during pregnancy be evaluated and managed after delivery?
Patients with gestational diabetes mellitus (GDM), who are at high risk of developing
impaired glucose tolerance (IGT) after delivery10, need to be evaluated for glucose
metabolism from early in the post‐partum period with a 75 g OGTT performed at between
6 and 12 weeks post‐delivery. Thereafter, they should be followed up on a routine
basis, but instructed on MNT and increased physical activity/exercise as required.
18
Pediatric/Adolescent Diabetes
Q18‐1 What is the basic treatment policy for pediatric/adolescent diabetes?
The treatment policy for pediatric/adolescent patients with diabetes is to accommodate
age‐specific differences in development/growth and comprehension, with sufficient
consideration given to the patient's mental immaturity1, 2.
Q18‐2 How is pediatric/adolescent type 1 diabetes diagnosed?
The diagnosis of pediatric/adolescent type 1 diabetes consists of demonstrating evidence
of progressively declining endogenous insulin secretion or its depletion; islet‐specific
autoantibodies have been shown to be present in the majority (70–90%) of patients3.
Q18‐3 How are pediatric/adolescent patients with type 1 diabetes to be treated?
The goal of treatment consists of preventing diabetic complications through glycemic
control as well as maintaining the patient's social and mental wellbeing1, 2.
In pediatric/adolescent patients with type 1 diabetes, insulin injection therapy is
indispensable and is therefore to be initiated immediately after the diagnosis has
been established1, 2.
MNT in pediatric/adolescent patients with type 1 diabetes is not primarily intended
to restrict the energy intake but rather to ensure the age‐ and gender‐specific intake
of energy that is necessary and sufficient for their normal development and growth1,
2.
All types of sport are recommended as physical activity/exercise for pediatric/adolescent
patients with type 1 diabetes as long as they have no advanced complications and their
glycemic control remains stable1, 2.
Hypoglycemia is likely to be associated with cognitive impairment. However, hypoglycemia
may not be recognized in patients below 6–7 years of age and may therefore become
severe. Thus, countermeasures need to be taken against hypoglycemia in these patients.
It should also be noted that persistent hyperglycemia is also associated with cognitive
impairment4.
Q18‐4 How is type 2 diabetes diagnosed in pediatric/adolescent patients?
An oral glucose tolerance test (OGTT) using glucose (body weight × 1.75) g (ideal
body weight may also be used; up to a maximum of 75 g) is to be performed in pediatric/adolescent
patients and their diagnosis is to be made according to the same glucose categories
and diagnostic criteria that are used in adult patients1.
Q18‐5 How are pediatric/adolescent patients with type 2 diabetes to be treated?
As in patients with type 1 diabetes, the goal of treatment consists of preventing
chronic diabetic complications through glycemic control as well as in maintaining
their social and mental wellbeing1, 5. Again, early intervention for multiple risk
factors is the key to preventing micro and macroangiopathy in these patients.
MNT in pediatric/adolescent patients with type 2 diabetes is not primarily intended
to restrict the energy intake but rather to ensure the age‐ and gender‐specific intake
of energy that is necessary and sufficient for their normal development and growth1,
5. In obese individuals, however, the energy intake is to be limited to 90–95% of
the intake required for their ideal body weight and to be nutritionally well‐balanced1,
6, while increased physical activity/exercise in these individuals is to primarily
involve aerobic exercise, thus increasing both their physical activity levels and
their energy consumption1, 6.
In patients with inadequate glycemic control despite MNT and physical activity/exercise,
pharmacotherapy is to be initiated1, 5. In patients with ketoacidosis or those with
inadequate glycemic control despite pharmacotherapy, insulin therapy is to be initiated1,
5. In patients with hypertension and dyslipidemia, appropriate therapy is to be implemented
for these conditions1, 5.
Q18‐6 How is neonatal diabetes diagnosed and treated?
Neonatal diabetes is broadly classified into transient and persistent phenotypes;
their diagnosis entails testing for the respective responsible genes7.
Sulfonylureas (SUs) have been shown to be effective in treating patients with KCNJ11/ABCCB8
gene mutations and to allow these patients to discontinue insulin therapy8, 9.
Q18‐7 How are pediatric/adolescent patients and their families to be supported?
Pediatric/adolescent patients are to be given optimal therapy, even at school1, 10.
Pediatric/adolescent patients are to participate in all school events and school administrators
are to ensure that their schools provide support for their participation10.
Given that mental/psychological factors have been shown to significantly affect the
patient's diabetes management and prognosis, mental/psychological counselling is to
be offered with sufficient care given to addressing individual differences in mental/psychological
maturity1, 2.
Immediately after affected patients have been diagnosed, their families are to be
fully instructed on their diabetes as well as the treatment policy decided on to address
their individual maturity10.
Diabetes camps are intended to offer support for pediatric patients to grow into independent
adults and include medically designed and recreational programs1.
19
Diabetes in Older Adults
Q19‐1 What are the characteristics of diabetes in older adults?
Older patients with diabetes are likely to be susceptible to postprandial hyperglycemia
and hypoglycemia and to be particularly vulnerable to hypoglycemia.
In patients with diabetes, older age tend to be associated with renal impairment,
which makes older patients susceptible to drug interactions.
In patients with diabetes, older age is often associated with geriatric syndromes
such as dementia/cognitive impairment, depression and sarcopenia.
CQ19‐2 Is glycemic control effective in suppressing vascular complications in older
patients with diabetes? (Figure 7)
Figure 7
Glycemic targets (HbA1c values) for older patients with diabetes. For older patients,
the glycemic target is to be determined for each patient by taking into account his/her
age, duration of diabetes, risk of hypoglycemia, and any support available to the
patient, as well as the patient's cognitive function, basic/instrumental activities
of daily living (ADL), and comorbidities/functional impairments, while noting the
potential risk of hypoglycemia that increases with age in each patient. (1) Refer
to the Japan Geriatrics Society website1, 2, for the evaluation of the cognitive function,
basic ADL (e.g., self‐care abilities such as dressing, transferring, bathing, and
toileting), and instrumental ADL (e.g., the patient's ability to maintain an independent
household by performing activities such as shopping, meal preparation, taking medication,
and handling finances). In end‐of‐life care, priority is to be given to preventing
significant hyperglycemia and subsequent dehydration and acute complications through
appropriate therapeutic measures. (2) As in other age groups, the glycemic target
for preventing diabetic complications in older patients with diabetes is set to <7.0%.
However, this can be set to <6.0% for those who are thought to be likely to achieve
glycemic control through MNT and/or physical activity/exercise alone or those who
are likely to achieve glycemic control with drug therapy without adverse reactions,
or 8.0% for those in whom intensifying therapy may prove difficult. In either case,
no lower limit is specified for the glycemic target. A glycemic target of <8.5% may
be allowed in patients who are thought to be in category III and therefore at risk
of developing adverse reactions to multi‐drug combination therapy or in those with
serious comorbidities or poor social support. (3) In patients in whom priority should
be given to preventing the onset/progression of diabetic complications due to their
duration of disease, the glycemic target or its lower limit may be set for each older
patient with appropriate measures in place to prevent severe hypoglycemia. Current
treatments are to be continued in those who are <65 years of age, even when their
HbA1c values fall below their glycemic target or a lower limit while on therapy; however,
care needs to be taken to monitor these patients for potential severe hypoglycemia.
Glinides may be classified as drugs that are unlikely to be associated with severe
hypoglycemia, as the onset of severe hypoglycemia varies depending on the type and
amount of glinide used in a particular patient relative to the patient's glucose level.
Given that hyperglycemia is a risk factor for both diabetic micro‐ and macroangiopathy
in older patients as well, appropriate glycemic control is to be implemented in these
patients1, 2. (Grade A by consensus: 100% agreement)
Q19‐3 Are hyperglycemia and hypoglycemia risk factors for cognitive impairment, dementia,
decreased activities of daily living (ADL) and depression in older patients?
Hyperglycemia and severe hypoglycemia are risk factors for cognitive impairment and
dementia in older patients3, 4.
Hyperglycemia is a risk factor for sarcopenia, falls and depression in older patients5,
while decreased HbA1c6 and hypoglycemia7 are associated with an increased risk of
falls in these patients.
Given that there is no clear evidence to show that reducing glucose levels leads to
the prevention of dementia8 or decreased ADL6, tight glycemic control should not be
implemented in older patients.
Q19‐4 Is MNT effective for achieving glycemic control in older patients with diabetes?
MNT has also been shown to be useful for correcting hyperglycemia, dyslipidemia, obesity
in older patients.
CQ19‐5 Is physical activity/exercise effective for achieving glycemic control and
maintaining the ADL and cognitive function of older patients with diabetes?
Physical activity/exercise (i.e., routine physical activity and walking) has been
shown not only correct metabolic disorders but also improve the life prognosis, reduce
cardiovascular disease, maintain ADL, and suppress cognitive impairment9. (Grade A:
100% agreement)
Resistance training has been shown to increase the lean body mass and muscle strength
and improve glycemic control in older patients with type 2 diabetes10. (Grade B: 100%
agreement)
Q19‐6 What are the precautions in implementing glucose‐lowering therapy in older patients?
Older patients receiving glucose‐lowering agent(s) are to be monitored for associated
adverse events such as hypoglycemia and their families and caregivers are to be instructed
on nonspecific symptoms of hypoglycemia and how to handle them as well as how to deal
with sick days.
The glucose‐lowering agents that are to treat older patients are to be chosen with
consideration given to their physical and cognitive function, socioeconomic status,
adherence and their (or their caregiver's) wishes and preferences.
The renal function of older patients is to be regularly assessed and their medications
are to be replaced or their doses adjusted accordingly.
Q19‐7 Are hypertension and dyslipidemia risk factors for other complications in older
patients with diabetes?
Hypertension is likely to be a risk factor for micro‐ and macroangiopathy and dyslipidemia
is likely to be a risk factor for macroangiopathy in older patients with diabetes.
20
Acute Metabolic Complications of Diabetes, Sick Days, and Infectious Diseases
Q20‐1 How is diabetic ketoacidosis (DKA) diagnosed and treated?
Diabetic ketoacidosis (DKA) is defined as a state that occurs as a consequence of
inadequate insulin action and increased insulin‐counterregulatory hormone secretion
and which requires emergency attention due to associated hyperglycemia (>250 mg/dL
[13.9 mmol/L]), ketosis (increased β‐hydroxybutyric acid), acidosis (arterial blood
pH, ≤7.30; bicarbonate ion [HCO3
–], ≤18 mEq/L)1, 2.
Patients presenting with DKA are to be appropriately managed with normal saline‐based
fluid and electrolyte (e.g., sodium chloride and potassium) replacement as required1.
As a rule, acidosis is not to be corrected in patients with DKA1, 2.
Patients presenting with DKA are to be given regular insulin as continuous intravenous
insulin infusions1, 2.
The use of bolus insulin injection in children is associated with the risk of cerebral
edema and is not recommended3.
Q20‐2 How is a hyperosmolar hyperglycemic state (HHS) diagnosed and treated?
A hyperosmolar hyperglycemic state (HHS) is associated with hyperglycemia (>600 mg/dL
[33.3 mmol/L]) and hyperosmolarity (effective osmolality, >320 mOsm/L) and potentially
mild ketosis (if present) but not severe ketoacidosis (arterial blood pH >7.30; HCO3
−, ≤18 mEq/L)2.
Patients presenting with HHS are to be appropriately managed with normal saline‐based
fluid and electrolyte replacement as required2.
As in DKA, patients presenting with HHS are to be given regular insulin as continuous
intravenous insulin infusions2.
Q20‐3 How is lactic acidosis (LA) diagnosed and treated?
Lactic acidosis (LA) is defined as a state of metabolic acidosis (arterial blood pH,
<7.35) due to the presence of a markedly increased lactic acid concentration (≥5.0
mmol/L) resulting from the overproduction or metabolic dysregulation of lactic acid
and requires emergency attention4.
Although LA is reported in patients receiving biguanides, the majority of these cases
occur in patients for whom biguanides should have been contraindicated or used with
caution5, 6.
Patients with LA should be treated for any underlying disease4.
In patients with LA, sufficient tissue blood flow and oxygenation should be ensured
with oxygen supplementation, artificial respiration, extracellular fluid replacement
or vasopressor therapy, as required4.
Q20‐4 How is hypoglycemia managed?
Patients exhibiting hypoglycemic symptoms, such as palpitation, sweating, weakness
or a decreased level of consciousness, or those with a usual glucose level of <70
mg/dL (3.9 mmol/L) should be diagnosed as having hypoglycemia and managed accordingly7.
Patients with hypoglycemia should be managed with oral carbohydrates (equivalent to
glucose 5–10 g), intravenous glucose infusion (equivalent to glucose 10–20 g), or
muscular glucagon injection. Hypoglycemia may recur or be prolonged, even after the
resolution of symptoms and therefore needs to be closely monitored and managed8.
Q20‐5 Are any infections typically associated with diabetes?
Infections such as emphysematous cholecystitis, organ or soft tissue abscesses, rhinocerebral
mucormycosis, malignant external otitis, emphysematous cystitis, emphysematous pyelitis,
necrotizing fasciitis and Fournier's gangrene tend to have diabetes as an underlying
disease9.
Q20‐6 How is glycemic control managed during infection?
Diabetes is associated with decreased multinuclear neutrophil migration, adhesion,
phagocytic and bactericidal capacity. Thus, infections tend to persist and become
severe in patients with poor glycemic control.
Hyperglycemia should be treated with insulin therapy in patients with a severe infection7,
10, 1. These patients must also be managed not only with fluid replacement and continuous
intravenous insulin infusion, but also with immediate treatment of any underlying
disease responsible for hyperglycemia from an early stage onwards (the primary infection
site and the causative bacteria are to be identified and appropriate agents are to
be chosen for the pathogen)1.
Q20‐7 Is vaccination recommended in patients with diabetes?
Influenza vaccination is recommended for patients with diabetes2.
Pneumococcal vaccination is recommended for patients with diabetes3.
Q20‐8 How are sick days to be managed?
Patients with diabetes should be encouraged to establish a connection with healthcare
facilities ahead of time to ensure that they will be available for consultation during
sick days1.
Patients with diabetes are to be instructed not to discontinue oral hypoglycemic agents
or insulin without their physicians’ instruction1.
When they have any problems with eating, patients with diabetes are to be encouraged
to consult healthcare facilities early and to receive appropriate instructions1.
Care is to be taken to make sure that patients with diabetes have a sufficient water
intake to prevent potential dehydration and that they consume a sufficient amount
of easily digestible carbohydrates (e.g., porridge, noodles and fruit juice) to ensure
a sufficient intake of energy1 during sick days.
Patients with diabetes are to be instructed to self‐monitor their glucose levels and
to have their ketone body levels measured as frequently as possible during sick days1.
21
Prevention of Type 2 Diabetes
Q21‐1 How are patients assessed to determine their risk of diabetes?
Various risk factors have been identified for diabetes, and a risk model (risk scores)
is currently being developed for type 2 diabetes in Japanese1, 2, 3.
Q21‐2 Are obesity and changes in body composition associated with the risk of type
2 diabetes?
Obesity and abdominal obesity4, weight gain5, 6, and low birthweight7, 8 are associated
with an increased risk of diabetes.
Q21‐3 Are physical activity and exercise habits associated with the risk of diabetes?
Strenuous physical activity in daily living9, aerobic exercises such as walking10
and exercise habits such as resistance‐exercise training1, 2 are associated with a
decreased risk of diabetes.
Q21‐4 Is the total energy and nutrient intake associated with the risk of diabetes?
Modification of dietary habits focusing on optimization of the total energy intake
is crucial to prevent type 2 diabetes3, 1, 2. An insufficient intake of dietary fibers
has been shown to be a risk factor for type 2 diabetes1, 2.
Q21‐5 Does the intake of alcoholic and other beverages affect the risk of type 2 diabetes?
Evidence from observational studies shows a U‐shaped correlation between the intake
of alcohol and the risk of diabetes3, 4. Thus, the intake of alcohol is to be limited
to within a reasonable range (equivalent to 20–25 g of ethanol per day)5, 6, 7. The
intake of soft drinks8, 9 has been shown to be associated with an increased risk of
diabetes. While the intake of coffee is highly likely to have a preventive effect
against the development of diabetes, the available evidence to support this is not
strong enough to include it among the recommendations.
Q21‐6 Do smoking and smoking cessation affect the risk of type 2 diabetes?
Smoking is an established risk factor for diabetes1. Smoking cessation is temporarily
associated with increased risk of diabetes due to associated weight gain but is associated
with a decreased risk of diabetes over the long term2, 3.
Q21‐7 Are psychosocial factors, such as stress and working environment, associated
with the risk of type 2 diabetes?
Mental stress4 and depressive tendencies (depression)5, 6 are associated with an increased
risk of diabetes. Working environmental factors, such as short sleep duration7 and
shift work8, are also risk factors for diabetes.
CQ21‐8 Does intervention with lifestyle modification prevents type 2 diabetes?
Intervention with lifestyle modification focused on adjustment of diet and exercise
habits has been shown to be effective in preventing type 2 diabetes3, 1, 2, 9, 10,
11. (Grade A: 100% agreement)
Q21‐9 Does pharmacotherapy prevent type 2 diabetes?
Biguanides12, α‐glucosidase inhibitors13, 14, and thiazolidinediones15 are shown to
be effective in preventing diabetes (In Japan, only voglibose has been covered by
health insurance for use in patients with impaired glucose tolerance [IGT] who are
considered to be at high risk of cardiovascular disease)16.