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217
and bladder cancer [8]. A recent study that
used Mendelian randomization to determine
the risk of diabetes and cancer in the Japanese
population did not provide strong evidence to
support this association [9]. Insulin resistance
and associated hyperinsulinemia, rather than
diabetes mellitus itself, may be implicated in
the increased risk of cancer.
1.9 Treatment
1.9.1 Objective
Antidiabetic therapy is aimed at prevention and
progression of complications, maintenance of
patients’ quality of life as closely as possible to
that of healthy individuals, and ensuring life
expectancy similar to that of healthy individuals.
Optimal blood glucose control and management
of complications, such as hypertension and lipids
are important to achieve these goals.
HbA1c<7.0% is considered the target level to
optimize glycemic control and prevent complications (Fig.12.2) [10]. Figure 12.3 shows details
regarding glycemic control in elderly patients
with diabetes [11].
1.9.2 Actual Treatment
Diet, exercise, and medication represent the cornerstones of diabetic care.
1. Dietary therapy: Energy intake is calculated
using the following formula: objective body
weight × physical activity [12]. In patients
aged <65years, the objective body weight is
calculated as (height [m])2 × 22. In patients
aged >65years, objective body weight is calculated as (height [m])2 × 22–25. Physical
activity is considered as 25–30kcal/kg objective body weight for light work, 30–35kcal/kg
objective body weight for normal work, and
>35kcal/kg objective body weight for heavy
work. A food exchange list [13] is a userfriendly guide and forms an important element
of actual dietary guidance. The amount of
food-derived energy is set at 80kcal/unit and
is described based on the unit (e.g., 1
unit=50g of boiled rice). Patients with hyper-
Fig. 12.2 Glycemic control targets. (Reproduced from [10])
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Fig. 12.3 Glycemic targets (HbA1c values) for elderly patients with diabetes. (Reproduced from [11])
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tension are recommended to consume <6g of
salt/day. A protein-restricted diet is required in
patients with progressive nephropathy.
2. Exercise therapy: Exercise increases utilization of
glucose and fatty acids and lowers blood glucose
levels and improves insulin sensitivity. Exercise
does not consume signicant amounts of energy;
therefore, increased exercise cannot utilize the
extra energy associated with overeating.
3. Pharmacotherapy: This therapeutic strategy
includes the administration of insulin secretagogues, non-insulin secretagogues, and insulin.
(a) Insulin secretagogues
• Sulfonylureas (SUs)
These drugs bind with SU receptors on
the pancreatic β-cell membrane and
promote insulin secretion.
• Glinides
These agents dissociate from SU receptors within a short time; therefore, they
stimulate insulin secretion during the
early postprandial period and thereby
improve postprandial hyperglycemia.
• Dipeptidyl peptidase-4 (DPP-4)
inhibitors
GLP-1 and GIP are rapidly degraded by
DPP-4; therefore, inhibition of DPP-4
activity increases endogenous GLP-1
and GIP production, promotes insulin
secretion in a glucose- dependent manner, and suppresses glucagon secretion.
• GLP-1 receptor agonists
These agents bind to GLP-1 receptors
on pancreatic β-cells and stimulate
insulin secretion in a blood glucosedependent manner. Reductions in food
intake and body weight are also
expected. Oral and subcutaneous formulations are available for administration once or twice daily or once weekly.
Mixed injections of GLP-1 receptor
agonist and insulin are also available.
• GIP and GLP-1 receptor agonist
Tirzepatide is a dual GIP and GLP-1
receptor agonist. Reduction in food
intake and body weight are also
expected.
• Imeglimin
This novel orally administered drug
was introduced in 2021 and is shown
to have an effect on the mitochondria.
It promotes insulin secretion in a blood
glucose-dependent manner and
improves insulin resistance in the liver
and skeletal muscles.
(b) Non-Insulin secretagogues
• Biguanides
These drugs suppress gluconeogenesis
in the liver, improve insulin sensitivity
in peripheral tissues, and inhibit glucose absorption in the gastrointestinal
tract. They are contraindicated in
patients with severe renal impairment
and should be withdrawn prior to
administration of contrast agents.
• Thiazolidinediones
These antidiabetic agents improve insulin resistance in adipose tissue and skeletal muscles. However, water retention
is a known adverse effect of this drug.
• Alpha-glucosidase inhibitors (α-GIs)
These agents inhibit α-glucosidase
activity and delay carbohydrate
absorption by inhibiting the degradation of disaccharides to monosaccharides, which reduces postprandial
hyperglycemia and insulin secretion.
The most common adverse effects of
α−GIs include gastrointestinal symptoms such as abdominal distention,
atus, constipation, and diarrhea.
• Sodium-glucose co-transporter 2
(SGLT2) inhibitors
These drugs inhibit glucose reabsorption by SGLT2 in the renal tubules and
promote urinary excretion of glucose,
thereby reducing hyperglycemia. The
weight loss associated with these
drugs is a benet in patients with obesity. Some of the SGLT2 inhibitors are
used in patients with heart failure and
chronic kidney disease.
(c) Insulin therapy
Advances in genetic engineering have
led to the emergence of novel insulin
preparations. Furthermore, owing to the
availability of innovative injection
equipment and widespread use of selfmonitoring blood glucose devices, insulin
therapy is easier to administer.
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1.10 Hypoglycemia
Hypoglycemia is a known adverse effect associated
with the use of SUs, glinides, or insulin; patients
should be instructed regarding prompt ingestion of
glucose or supplemental food in such cases.
1.11 Metabolic Syndrome
Metabolic syndrome is characterized by insulin
resistance. In Japan, patients who show accumulation of visceral fat and meet ≥two of the following
criteria are diagnosed with metabolic syndrome:
impaired glucose tolerance, impaired lipid metabolism, and hypertension (Fig.12.4) [14].
1.12 Notes fromDentistry
Perspective
KoichiroUeki,KunioYoshizawa,
TadashiToyama
1.12.1 Precautions onDental
Treatment
1. Removing psychological and painful stress
Hormones such as adrenocorticotropic
hormone, thyroid-stimulating hormone, and
catecholamines secreted by stress have hyperglycemic effects, so it is important to engage
in dental treatment to avoid psychological or
painful stress as much as possible [15]. In
addition, HbA1c level is generally empha-
sized as a major index of glycemic control
(see Fig.12.2), because it reects the average
blood glucose level over the past month or
two, hyperglycemia may occur with treatment
even if the HbA1c level is within the control
target. Therefore, it is advisable to refer to
fasting blood glucose and postprandial blood
glucose to judge the patient’s metabolic state
comprehensively during treatment.
2. Be aware of periodontitis and other
infections
Diabetes mellitus treatment may signicantly reduce bleeding on probing (BOP) in
periodontal tissues and improve inammation
of periodontitis. It is rated as a recommended
grade B for the CQ “Is diabetes treatment
effective in ameliorating periodontal disease?”
in Diabetes practice guidelines [16]. In addition, periodontitis is a risk factor for worsening glycemic control and progression of
diabetes mellitus by increasing insulin resistance through inammatory cytokines derived
from bacterial infection [17]. On the other
hand, it is known that periodontal disease
tends to be more severe in diabetic patients,
and the main reason is thought to be that macrophage function and bacterial phagocytosis of
neutrophils, which are the infection defense
functions of the body, are decreased by hyperglycemia and ischemia, and the growth of
periodontal pathogens cannot be controlled
[17]. Therefore, thorough prevention and treatment of periodontitis are indispensable in the
dental treatment of diabetic patients.
Fig. 12.4 Diagnostic
criteria of metabolic
syndrome in Japan.
(Modied from [14])
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3. Sufcient attention should be paid to local
bleeding
Diabetic patients often suffer from complications of atherosclerotic diseases such as
stroke and angina pectoris, and many of them
take antiplatelet and anticoagulant drugs for
their treatment. If the risk of thrombosis associated with the discontinuation of these antithrombotic agents is judged to be greater than
the risk of bleeding, it is advisable to perform
surgical treatment with careful attention to local
hemostasis while continuing the medication.
4. Treatment time setting
To prevent hypoglycemia associated with
skipping meals, consideration should be given
to the start time of the procedure. Outpatient
dental procedures should be scheduled to begin
around 1h and 30min after breakfast or lunch,
and patients should be able to eat at their usual
time before and after the procedure [15].
5. What to do in case of hypoglycemia
Hypoglycemia is a common emergency
during treatment of diabetes mellitus, especially in dental patients, who often suffer from
hypoglycemia due to poor food intake caused
by dental pain or restricted food intake after
oral surgery. Hypoglycemia may also be
caused by insulin injections or oral hypoglycemic agents in the management of diabetes
mellitus. If hypoglycemic symptoms such as
sweating, anxiety, palpitations, tremor, pallor,
and drowsiness are observed, blood glucose
should be measured and glucose should be
administered. When disturbance of consciousness occurs, blood glucose monitoring is necessary to differentiate from hyperglycemic
coma. If hypoglycemia occurs to the extent
that the level of consciousness is decreased,
even if the patient recovers temporarily with
emergency treatment, there is a high possibility that the hypoglycemia will recur or prolong. If oral intake is possible, glucose (10g)
should be given. Sucrose requires at least
double that amount (20 g), and other sugars
delay the onset of effects. If oral intake is not
possible or in an emergency, administer
20mL of 50% glucose (40 mL of 20% glucose) intravenously. Hypoglycemia induced
by sulfonylureas (SU) tends to be delayed,
and hypoglycemic symptoms may recur after
awakening. In addition, if the patient is taking
an α-glucosidase inhibitor, glucose should
always be chosen because sucrose delays the
increase in blood glucose [18].
1.12.2 On theUse ofLocal Anesthetics
andEpinephrine
A local anesthetic (lidocaine hydrochloride) containing epinephrine, a vasoconstrictor, is frequently used because of its high peripheral
vasoconstrictor and anesthetic effects, but the
stimulation of epinephrine is known to increase
blood glucose by predominantly inhibiting insulin secretion [15]. Epinephrine-containing local
anesthetics (lidocaine hydrochloride), which
have high peripheral vasoconstrictor and anesthetic effects, can be used as usual in patients
who receive only diet therapy or whose blood
glucose is well controlled. However, if blood glucose control is poor or there are complications in
the circulatory system or cerebrovascular disease, the use of 1–2 cartridges (1.8–3.6 mL)
should be limited depending on the severity of
the disease, or propitocaine hydrochloride containing felypressin should be used instead of
lidocaine hydrochloride containing epinephrine.
However, felypressin-containing local anesthetics are less vasoconstrictive and have a slightly
lower anesthetic effect. Therefore, in some situations, it may cause painful stress to the patient,
which may lead to adverse consequences such as
increased blood pressure and blood glucose.
1.12.3 Oral Complications
There have been many reports of clostridial
infection in the deep cervical region and severe
dental infections in diabetic patients after tooth
extraction. It should be noted that diabetic
patients are more likely to have more serious dental infections than healthy people when their
immunity is weakened. For example, if odontogenic infection arising from an untreated stump
of tooth spreads to adjacent organs (Fig.12.5), or
if sepsis occurs, it may be fatal. For this reason,
early treatment of dental infections in diabetic
patients is recommended.
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a
c
d
b
Fig. 12.5
serious in diabetic patients than in normal subjects.
Therefore, patients should pay attention to adequate oral
cleaning and dental treatment of any oral infection foci
before they worsen. (a) CT scan: swelling with gas production was observed from the lower orbit to the buccal
area. (b, c) Patient with type 1 diabetes mellitus: The
patient came to our hospital for cellulitis caused by peri-
(a–f) Dental infections are more likely to be
odontitis in the right maxillary molar. The blood glucose
was in the 500 mg/dL range and CRP was 20.9 mg/dL.
Gas-producing Bacteroides was detected. (d, e) The
patient required antimicrobial therapy, incision and drainage, and tooth extraction. (f) Intraoral photograph (mirror
image): after removal of the causative tooth. Poor intraoral cleanliness and numerous remaining roots were
observed
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e
f
Fig. 12.5 (continued)
1.12.4 What toDo inaSituation Where
It Is Better toExtract aTooth
Even withaHigh HbA1c
According to the training guidebook for medical
specialists of the Japanese Diabetes Association,
preoperative glycemic control goals include fasting blood glucose <140 mg/dL, postprandial
blood glucose <200mg/dL, negative urine ketone
bodies, and the amount of urinary glucose, but
there is no clear indicator for HbA1c. Because
high HbA1c levels are often associated with poor
fasting and postprandial glucose control, it is
advisable to improve glycemic control through
inpatient management, continuation or introduction of insulin therapy, and improvement of diet
and medication adherence before performing
tooth extraction. If surgical stress is expected to
be large, or if tooth extraction surgery under general anesthesia is indicated, the patient should be
hospitalized 3–7 days before surgery to control
the blood glucose level adequately.
If the HbA1c is high and there is a concern that
postponing a surgical procedure such as tooth
extraction will worsen the local condition and
affect the general condition, it should be performed
with adequate perioperative infection control and
close coordination to the attending physician.
Basically, the incidence of surgical site infection
(SSI) in diabetic patients with appropriately con-
trolled blood glucose, such as HbA1c (NGSP) less
than 7.0%, is similar to that in healthy subjects, so
there is no need to choose broad-spectrum antimicrobial therapy. However, because of the risk of
perioperative infection in diabetic patients with
poor glycemic control, more attention should be
paid to the prevention of perioperative wound
infection, such as administering antimicrobial
agents from the day before tooth extraction [19].
2 Dyslipidemia
YasushiIshigaki
2.1 General Statement ofLipid
Metabolism
Cholesterol and triglycerides (TG) are considered as the major lipids associated with dyslipidemia. Cholesterol is an essential component of
cell membranes and is also used to produce bile
acids, adrenocortical hormones, and sex hormones. On the other hand, TG is a combination
of free fatty acids and glycerol, contributing to
energy storage.
In general, lipids are insoluble in water. Since
lipids cannot exist in the blood in their original
form, cholesterol and TG are encapsulated in phospholipids and dissolved in the blood as the form of
lipoproteins. Lipoproteins are roughly classied
into ve types according to the composition and
content of lipids as well as the type of apoprotein
(Fig.12.6). Chylomicrons and VLDL, which have-
low specic gravity, contain a large proportion of
TG, while LDL and HDL, which have high specic
gravity, contain a large proportion of cholesterol.
There are three pathways in lipid metabolism:
the exogenous pathway, the endogenous pathway, and the reverse cholesterol transport pathway (Fig. 12.7). In the exogenous pathway,
dietary lipids are absorbed from the small intestine, and owing into the body circulation as
chylomicrons, are nally to be hydrolyzed by
lipoprotein lipase (LPL) before being taken up
by the liver. In the liver, TG and cholesterol are
synthesized independently of the lipids taken up
from the blood, and both are combined and
released into the blood as VLDL particle. VLDL
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Types of
lipoproteins
Role Transporting lipids
Diameter(Å) 80010,000 30080025030020025075200
Structural
component
Triglyceride
Cholesterol
Fig. 12.6
Types of lipoproteins
CM VLDL IDL LDL HDL
Chylomicron Very low density
lipoprotein
Released from the
ingested through
the diet to the
liver
liver to provide free
fatty acids
Intermediate
density
lipoprotein
Intermediates
between VLDL
and LDL
Low density
lipoprotein
Supply
cholesterol to
peripheral tissues
High density
lipoprotein
Draws excess
cholesterol from
peripheral tissues
and redistributes
it
exogenous pathway
meal
small
intestine
chylomicron
B–48
bile acid
remnant
receptor
chylomicron
remnant
E
liver
B–48
LDL
receptor
E
LPL
C II
Fig. 12.7 Lipoprotein metabolic pathway
is metabolized to IDL and LDL by LPL, and
supplies free fatty acids and cholesterol to
peripheral tissues. This is called the endogenous
pathway. The reverse cholesterol transport path-
reverse cholesterol transport pathway
A II
A I
HDL
B–100
LPL
C II
CETP
B–100
HTGL
IDLVLDL LDL
E
endogenous pathway
C II
peripheral
tissue
B–100
way plays a role of HDL in collecting excess
cholesterol from peripheral tissues and returning
it to the liver or redistributing it to VLDL and
LDL.
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2.2 Diagnosis ofDyslipidemia
In clinical practice, three or four lipid parameters
are measured: total cholesterol (TC), TG, HDL
cholesterol (HDL-C), and LDL cholesterol
(LDL-C). Dyslipidemia is dened as hyper-LDL C (high cholesterol in the LDL fraction), hyper TG (high total TG of all lipoproteins combined),
hypo-HDL-C (low cholesterol in the HDL fraction), and hyper-non-HDL-C (high total cholesterol minus HDL-C). The reference values for
diagnosing abnormalities are LDL-C 140mg/dL
or more, TG 150 mg/dL or more, HDL-C less
than 40 mg/dL, and non-HDL-C 170 mg/dL or
more (Table 12.2), and early morning fasting
blood sampling is recommended for diagnosis
[20].
2.3 Pathogenesis ofDyslipidemia
Dyslipidemia is often caused by overeating,
heavy alcohol consumption, lack of exercise, and
obesity, as in other lifestyle-related diseases.
Some kinds of dyslipidemias associated with
genetic abnormalities, referred to as primary dyslipidemias, show severe lipid abnormalities.
Familial hypercholesterolemia (FH) is one of the
most frequent and important genetic disorders of
lipid metabolism. It is characterized by (1) high
serum LDL-C (180 mg/dL or higher is suspicious, 250 mg/dL or higher is strongly suspicious), (2) xanthomas (e.g., Achilles tendon
thickening), and (3) a family history of FH or
coronary artery disease which developed in relatively young age (exhibit an autosomal dominant
inheritance). Early intervention for FH is strongly
recommended because of the high risk of developing coronary artery disease at a young age. In
addition, family screening is also useful to nd
FH. There are some secondary lipid disorders
associated with other diseases. Hypothyroidism
Table 12.2 Serum lipid diagnostic reference values
LDL cholesterol 140mg/dL or more
Triglyceride More than 150mg/dL
HDL cholesterol Less than 40mg/dL
Non-HDL cholesterol 170mg/dL or more
and nephrotic syndrome are the most common
disorders in which LDL-C is elevated. Diabetes
mellitus often causes an increase in TG levels.
Corticosteroid drugs may increase LDL-C and
TG.
2.4 Symptoms ofDyslipidemia
Most of patients with dyslipidemia are asymptomatic. However, dyslipidemia is generally recognized as a risk factor for atherosclerotic
diseases such as coronary artery disease and cerebral infarction. In particular, hyper LDLcholesterolemia has a strong impact on
atherosclerosis, thereby, an important target for
treatment. Since hypertriglyceridemia (increase
in chylomicrons) is a risk factor for acute pancreatitis, drug therapy should be started as soon as
possible if the blood concentration exceeds
1000mg/dL.
2.5 Management Goals
forDyslipidemia
Even if serum lipid levels exceed the reference
values shown in Table12.2, not all patients are
indicated for drug therapy. In accordance with
the Japan Atherosclerosis Society Guidelines for
Prevention of Atherosclerotic Cardiovascular
Diseases [20], each patient is stratied according
to their risk for establishing their LDL-C management target. At rst, LDL-C management target for patients with the history of coronary artery
disease, determined as secondary prevention, is
established as less than 100 mg/dL, especially,
less than 70mg/dL for those with FH, acute coronary syndrome, or high-risk diabetes. For patients
with primary prevention, if the patient has diabetes, chronic kidney disease, cerebrovascular disease, or peripheral arterial disease, LDL-C of less
than 120mg/dL should be established as the target. In the absence of any of the aforementioned
concomitant diseases, the risk for predicting coronary artery disease is classied into high, intermediate, and low risk groups by calculating their
itemized risks (age, gender, smoking status,
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blood pressure, HDL-C level, LDL-C level, presence of glucose intolerance, and presence of family history of coronary artery disease) in
accordance with Japan Atherosclerosis Society
Guidelines. The LDL-C management target values are less than 120 mg/dL, 140 mg/dL, and
160 mg/dL, respectively. The management targets for TG and HDL-C are <150 mg/dL and
≥40mg/dL, respectively.
2.6 Treatment ofDyslipidemia
For all patients with dyslipidemia, lifestyle modication is required. It is recommended that total
dietary energy intake should be optimized. In
addition, it is also recommended that the maintenance for range of both fat/energy ratio 20–25%,
and saturated fatty acids be 4.5–7%, restriction of
cholesterol intake below 200 mg/day, increase
for n-3 polyunsaturated fatty acids intake, and
restriction of alcohol intake below 25 g/day as
ethanol intake. Moreover, exercise therapy in
combination with aerobic exercise, such as fast
walking and swimming, and strength training is
also recommended.
If lipid management is insufcient after
3–6months of lifestyle modication, drug therapy should be considered. The most common
drugs are HMG-CoA reductase inhibitors
(statins), which act mainly by inhibiting cholesterol synthesis in the liver and increasing LDL
uptake from the blood. They are the standard
drugs for the treatment of dyslipidemia because
of their strong LDL-C-lowering effect and many
clinical results in reducing atherosclerotic diseases development. Muscle-related adverse
effects, such as myalgia, weakness, and CK elevation, are characteristic, and in severe cases,
rhabdomyolysis may occur. Ezetimibe, which
inhibits cholesterol absorption from the small
intestine, is also used as an LDL-C lowering
agent. Recently, PCSK9 inhibitors, which have a
very potent LDL-C-lowering effect, have been
used in some high-risk patients. Fibrates, which
inhibit TG synthesis in the liver and promote TG
degradation in the blood, are used in patients with
hypertriglyceridemia.
Because dyslipidemia is asymptomatic,
patients often do not participate in medical care
or discontinue treatment. Therefore, it is important to raise awareness for importance of disease
treatment even if the serum lipid level is normalized by medication.
2.7 Notes fromDentistry
Perspective
TakayoshiSakai
2.7.1 Dyslipidemia andOral Diseases
Dyslipidemia, also known as hyperlipidemia, is a
condition in which the amount of cholesterol,
neutral fat (triglycerides) and other lipids in the
blood is higher than a certain standard. An excess
of lipids in the blood tends to cause arteriosclerosis, which increases the risk of myocardial infarction and cerebrovascular disease. When patients
with hypertension, which exerts strong pressure
on blood vessels, develop dyslipidemia, their
blood vessel walls are more easily damaged,
increasing the risk of atherosclerosis. When insulin is insufcient due to diabetes mellitus, it
becomes difcult for the body to utilize triglycerides. The increase in triglycerides in the blood
tends to lead to dyslipidemia and the progression
of arteriosclerosis. There are few subjective
symptoms in patients themselves, and “sluggish
blood” is generally applied to the condition. If
the disease is discovered too late, it is not uncommon for patients to suffer a sudden attack such as
a myocardial infarction. As a preventive measure,
it is important to pay attention to lifestyle habits
such as exercise and diet, and to take early action
without delay if “suspicion of dyslipidemia” is
pointed out in a medical checkup. It is clear that
damage to blood vessels and blood ow caused
by the progression of atherosclerosis can cause
damage to the entire body, including the oral cavity. In this chapter, we will discuss the relationship between dyslipidemia and oral diseases.
Dyslipidemia and arteriosclerosis
According to the Vital Statistics of the Ministry
of Health, Labour and Welfare in 2009, the lead-
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