Learning Outcome

1. Discuss the incidence of diabetes.

2. Multi-causes of Diabetes.
3. List screening and diagnostic criteria for diabetes.
4. Discuss therapeutic goals for blood glucose, blood pressure, and lipids for a
patient with diabetes.
5. Recommend non pharmacologic therapies, including meal planning and physical
activity, for patients with diabetes.
FARMAKOTERAPI – Semester V/2015-2016

Diabetes Mellitus @AzizahVonna,MPharmSci.,Apt
Azizah Vonna, M. Pharm. Sci., Apt. 2

Learning Outcome Diabetes Mellitus - Definition

6. Compare oral agents used in treating diabetes by their mechanisms of action,
time of action, side effects, contraindications, and effectiveness. • Chronic metabolic disorders characterized by
7. Select appropriate insulin therapy based on onset, peak, and duration of action hyperglycemia
8. Discuss the signs, symptoms, and treatment of hypoglycemia. • May result in microvascular, macrovascular, and
9. Define diabetic ketoacidosis and discuss treatment goals. neuropathic complications.
10. Develop a comprehensive therapeutic monitoring plan for a patient with • Generally arises from a combination of insulin resistance
diabetes based on patient-specific factors. and β-cell dysfunction

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
3 4
Diabetes Mellitus - Prevalence

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
5 6

Other forms of diabetes mellitus

Tabel 3.5.3
Prevalensi diabetes, hipertiroid pada umur ≥15 tahun dan hipertensi pada umur ≥18 tahun
menurut provinsi, Indonesia 2013
Hipertensi
Provinsi Diabetes Hipertiroid
Wawancara Pengukuran
D D/G D D D/O U
Aceh 1,8 2,6 0,3 9,7 9,8 21,5
Sumatera Utara 1,8 2,3 0,3 6,6 6,7 24,7
Sumatera Barat 1,3 1,8 0,3 7,8 7,9 22,6
Riau 1,0 1,2 0,1 6,0 6,1 20,9
Jambi 1,1 1,2 0,2 7,4 7,4 24,6
Sumatera Selatan 0,9 1,3 0,1 7,0 7,0 26,1
Bengkulu 0,9 1,0 0,2 7,8 7,9 21,6
Lampung 0,7 0,8 0,2 7,4 7,4 24,7
Bangka Belitung 2,1 2,5 0,4 9,9 10,0 30,9
Kepulauan Riau 1,3 1,5 0,2 8,8 8,8 22,4
DKI Jakarta 2,5 3,0 0,7 10,0 10,1 20,0
Jawa Barat 1,3 2,0 0,5 10,5 10,6 29,4
Jawa Tengah 1,6 1,9 0,5 9,5 9,5 26,4
DI Yogyakarta 2,6 3,0 0,7 12,8 12,9 25,7
Jawa Timur 2,1 2,5 0,6 10,7 10,8 26,2
Banten 1,3 1,6 0,4 8,6 8,6 23,0
Bali 1,3 1,5 0,4 8,7 8,8 19,9
Nusa Tenggara Barat 0,9 1,3 0,2 6,7 6,8 24,3
Nusa Tenggara Timur 1,2 3,3 0,4 7,2 7,4 23,3
Kalimantan Barat 0,8 1,0 0,1 8,0 8,1 28,3
Kalimantan Tengah 1,2 1,6 0,2 10,6 10,7 26,7
Kalimantan Selatan 1,4 2,0 0,2 13,1 13,3 30,8
Kalimantan Timur 2,3 2,7 0,3 10,3 10,4 29,6
Sulawesi Utara 2,4 3,6 0,5 15,0 15,2 27,1
Sulawesi Tengah 1,6 3,7 0,4 11,6 11,9 28,7
Sulawesi Selatan 1,6 3,4 0,5 10,3 10,5 28,1
Sulawesi Tenggara 1,1 1,9 0,3 7,6 7,8 22,5
Gorontalo 1,5 2,8 0,3 11,1 11,3 29,0
8
Sulawesi Barat 0,8 2,2 0,3 9,5 9,6 22,5
Maluku 1,0 2,1 0,2 6,6 6,8 24,1
Maluku Utara 1,2 2,2 0,2 6,9 7,0 21,2
Papua Barat 1,0 1,2 0,2 5,0 5,2 20,5 @AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
Papua 0,8 2,3 0,2 3,2 3,3 16,8
7 8
Indonesia 1,5 2,1 0,4 9,4 9,5 25,8

Dari tabel 3.5.4 terlihat prevalensi diabetes melitus berdasarkan diagnosis dokter dan gejala
meningkat sesuai dengan bertambahnya umur, namun mulai umur ≥65 tahun cenderung menurun.
Prevalensi hipertiroid cenderung meningkat seiring bertambahnya umur dan menetap mulai umur
≥45 tahun. Prevalensi hipertensi berdasarkan terdiagnosis tenaga kesehatan dan pengukuran
terlihat meningkat dengan bertambahnya umur. Prevalensi DM, hipertiroid, dan hipertensi pada
 CHAPTER 43 | DIABETES MELLITUS 759

do not have insulin resistance, but antibodies are present in
the blood that are known to destroy pancreatic β cells.
C-peptide is the abbreviation for “connecting peptide.”
C-peptide is made when proinsulin is split into insulin and
C-peptide. They split before proinsulin is released from endo-
Drugs that increase blood glucose Drugs that increase blood glucose (cont)
cytic vesicles within the pancreas—one C-peptide for each
insulin molecule. Routine measurement of C-peptide levels,
insulin levels, and proinsulin are not recommended in most
patients.9 However, C-peptide measurements can be used to
distinguish between T1DM and T2DM. People with T1DM
have C-peptide levels below 1 ng/mL (0.33 nmol/L), whereas
those with T2DM will have values greater than 1 ng/mL
(0.33 nmol/L).
Categories of increased risk for diabetes (commonly
referred to as prediabetes) include impaired fasting glucose
(IFG), impaired glucose tolerance (IGT), or hemoglobin
A1c (A1c) between 5.7% and 6.4% (0.057 and 0.064; 39 and
46 mmol/mol hemoglobin [Hb]).10 IFG is defined as having a
fasting blood glucose (FBG) level between 100 and 125 mg/dL
(5.6 and 6.9 mmol/L). IGT is defined by a postprandial blood
glucose level between 140 and 199 mg/dL (7.8 and 11.0 mmol/L).
It is currently estimated that 70 million persons in the United
States have prediabetes.3 The development of IFG, IGT, or A1c
between 5.7% and 6.4% (0.057 and 0.064; 39  and 46 mmol/
mol) places the individual at high risk of eventually developing
diabetes. Because progression to diabetes is not predictable,
9
early interventions are gaining popularity.
T2DM is usually slow and progressive in its development.
Risk factors for T2DM include:
@AzizahVonna,MPharmSci.,Apt
9 t First-degree family history of DM (i.e., parents or
siblings)
t Overweight or obese
t Habitual physical inactivity
t Race or ethnicity (Native American, Latino or Hispanic
American, Asian American, African American, and
Drugs that decrease blood glucose Pacific Islanders)
t Previously identified IFG, IGT, or A1c between 5.7% and
6.4% (0.057 and 0.064 or 39 and 46 mmol/mol Hb)
t Hypertension (greater than or equal to 140/90 mm Hg or
on therapy for hypertension)
t High-density lipoprotein (HDL) less than 35 mg/dL
(0.91 mmol/L) and/or a triglyceride level greater than
250 mg/dL (2.83 mmol/L)
t History of gestational diabetes or delivery of a baby
weighing greater than 4 kg (9 lb)
t History of cardiovascular disease
t History of polycystic ovarian syndrome
t Other conditions associated with insulin resistance
(e.g., acanthosis nigricans)10
Gestational diabetes mellitus (GDM) is defined as
glucose intolerance in women during pregnancy. This
complication develops in between 2% and 10% of all preg-
nancies. 3 Women who have GDM have a 35% to 60% chance
of developing T2DM. Clinical detection of and therapy for
GDM are important because blood sugar control produces
significant reductions in perinatal morbidity and mortal-
ity. New diagnostic criteria call for all pregnant women not
previously known to have diabetes to undergo screening
for GDM between 24 and 28 weeks of gestation.11 Use of
these criteria resulted in an 18% GDM diagnosis rate in
one multinational epidemiologic study
10 that enrolled 25,000
pregnant women.12
Diabetes from other causes includes genetic defects in
@AzizahVonna,MPharmSci.,Apt
β-cell function, genetic defects in insulin action, diseases of
10
the exocrine pancreas such as cystic fibrosis, and drug- or
chemical-induced diabetes.10 Table 43–1 contains a list of
medications that may affect glycemic control.13 Although the
use of these medications is not contraindicated in persons
with DM, caution and awareness of the effects on blood
glucose should be taken into account when managing these
patients.

Diabetes Mellitus - Secondary Causes

Table 43–1
Medications That May Affect Glycemic Control13

Drug Effect on Glucose Mechanism or Comment

Angiotensin-converting enzyme inhibitors Slight reduction Improves insulin sensitivity
Alcohol Reduction Reduces hepatic glucose production
α-Interferon Increase Unclear
Diuretics Increase May increase insulin resistance
Glucocorticoids Increase Impair insulin action
Nicotinic acid Increase Impairs insulin action, increases insulin resistance
Oral contraceptives Increase Unclear
Pentamidine Decrease, then increase Toxic to β cells; initial release of stored insulin, then depletion
Phenytoin Increase Decreases insulin secretion
β-blockers May increase Decreases insulin secretion
Salicylates Decrease Inhibition of I-kappa-B kinase-β (IKK-β) (only high doses,
e.g., 4–6 g/day)
Sympathomimetics Slight increase Increased glycogenolysis and gluconeogenesis
Clozapine and olanzapine Increase Decreases insulin sensitivity; weight gain

This list is not inclusive of all medications reported to cause glucose changes.
11

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
11 12
 Diabetes Mellitus Diabetes Mellitus - Etiology
1. Diabetes is characterised by:
• a complete lack of insulin,
• a relative lack of insulin, or
• insulin resistance as well as disorders of other hormones.

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
13 14

Diabetes Mellitus - Complications Diabetes Mellitus - Etiology

Present in > 80% of people
with type 2 diabetes1
Lifestyle
• A sedentary lifestyle
Insulin
Approximately doubles
resistance IR the risk of a cardiac event2 • greater consumption of high-fat, high-carbohydrate
foods
Implicated in almost half of
CHD events in individuals • less physical activity.
with type 2 diabetes2

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
15 16
 Diabetes Mellitus - Lifestyle Diabetes Mellitus - Complications

Greene, R.J., Pathology and Therapeutics for Pharmacists, 3rd edition, 2008

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
17 18

Diabetes Mellitus - Complications Normal Carbohydrate Metabolism

▪ Glucose as body’s main fuel

Hyperglycemia o Cells metabolize glucose ⇥ glycolysis and the
Dyslipidemia Krebs cycle ⇢ adenosine triphosphate (ATP) as
energy
Hypertension
Insulin
resistance
IR Damage to blood 

▪ Glucose is stored in
vessels o the liver and muscles as glycogen
o stored in adipose tissue (breakdown through lipolysis)
Clotting abnormalities
Atherosclerosis ▪ Proteins also can be converted to glucose
Inflammation
through gluconeogenesis

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
20
 Insulin dan Diabetes Mellitus
Sumber Insulin: pankreas → sel islet (pulau-pulau Langerhans)

Sel-sel pulau-pulau Langerhans:

▪ Sel α
▪ Sel β
▪ Sel δ
▪ Sel Polipeptida pankreas
(PP)

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
21 22

Insulin dan Diabetes Mellitus

Sel α: Sel β:
Mensekresi insulin dan juga
▪ mensekresi glukagon →
amylin
hiperglikemia
▪ memecahkan protein otot
Sekresi distimulasi oleh:
Sekresi distimulasi oleh: ▪ glukosa
▪ makanan tinggi protein ( asam amino) ▪ hormon-hormon GIT
▪ adrenaline (melalui β adrenoseptor) ▪ dihambat oleh adrenalin (melalui α2
▪ rendahnya glukosa adrenoceptor)

Pulau-Pulau Langerhans

Kumar, Vinay., 2010, Robbins and Cotran Pathologic Basis of Disease

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
23 24
 Rang, H.P., 2012, Rang and Dale’s Pharmacology

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
25 26

Insulin Secretion Insulin Secretion

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
27 28
 Normal Insulin Action Normal Insulin Action
❖ Fasting insulin levels : 43 to 186 pmol/L (6 to 26 μIU/mL) ❖ The insulin-secretion response occurs in two phases.
❖ After food is consumed, blood glucose levels rise, and the insulin- • The second phase of insulin response
secretion response occurs in two phases. - gradual increase in insulin secretion, which lasts 60 to 120
• First phase insulin response, minutes
- 5 to 10 minutes - stimulates glucose uptake by peripheral insulin-dependent tissues
- suppress hepatic glucose production and
- cause insulin- mediated glucose disposal in adipose tissue. Slower release of insulin allows the body to respond to the new
glucose entering from digestion while maintain- ing blood glucose
This bolus of insulin minimizes hyperglycemia during meals and during
levels.
the postprandial period.
@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
29 30

Amylin Amylin
Sel β:
Mensekresi insulin dan juga
amylin

▪ People with diabetes have either a relative or complete lack

of amylin.
▪ Amylin mechanisms of action:
▪ suppression of postmeal glucagon secretion;
▪ regulation of the rate of gastric emptying, increases satiety;
▪ regulation of plasma glucose concentrations in the
Pulau-Pulau Langerhans bloodstream.

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
31 32
Diabetes Mellitus - Pathophysiology Diabetes Mellitus - OAD
α-glucosidase 
 Sulfonylureas/

inhibitors meglitinides Biguanides Thiazolidinediones
Diabetes is characterised by:
1. a complete lack of insulin, or relative lack of insulin,
2. insulin resistance
3. impaired Glucagon Secretion
↓ Insulin 

4. metabolic Syndrome ↓ Carbohydrate 

breakdown/

↑ Insulin 

secretion
↓ Glucose 

output resistance
absorption ↓ Insulin resistance
5. incretin Effect

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
33 34

Diabetes Mellitus - Impaired Insulin Secretion Diabetes Mellitus - Impaired Insulin Secretion
Genetic susceptibility, Normal IGT* Type 2 diabetes
obesity, Western lifestyle

Insulin Increased insulin


resistance resistance

Insulin
resistance IR β β-cell
dysfunction Insulin Hyperinsulinemia,
secretion then β-cell failure

Post-prandial
glucose Abnormal
glucose tolerance

Fasting
Hyperglycemia
Type 2 diabetes glucose

*IGT = impaired glucose tolerance

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
35 36
Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000.
 Diabetes Mellitus - Insulin Resistance
Insulin Resistance
Diabetes Mellitus - Impaired Glucagon Secretion
Insulin
resistance
IR
Sel α:
▪ mensekresi glukagon →
Liver Muscle Adipose
 hiperglikemia
tissue ▪ memecahkan protein otot
Sekresi distimulasi oleh:
↑ Glucose output ↓ Glucose uptake ↓ Glucose uptake ▪ makanan tinggi protein ( asam amino)
▪ adrenaline (melalui β adrenoseptor)
▪ rendahnya glukosa

Pulau-Pulau Langerhans
Hyperglycemia
Kumar, Vinay., 2010, Robbins and Cotran Pathologic Basis of Disease

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
38
Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000.

Diabetes Mellitus - Impaired Glucagon Secretion Diabetes Mellitus - Metabolic Syndrome CHAPTER 43 | DIABETES MELLITUS 761

Table 43–2 Clinical Presentation and Diagnosis of

Five Components of Metabolic Syndrome19 Diabetes Mellitus
▪ The release of insulin and the inhibition of glucagon is glucose stimulated
Risk Factor Defining Level Type 1 Type 2
▪ Most patients with a 10- to 20-year history of T1DM have lost their ability to release 1. Abdominal obesity Diabetes Diabetes
Characteristic Mellitus Mellitus
glucagon t Men Waist circumference greater than 102 cm
(40 in)
t Women Waist circumference greater than 89 cm Usual age of Childhood or Adult
▪ People with T2DM have (35 in) onset adolescence
2. Triglycerides Greater than or equal to 150 mg/dL Speed of onset Abrupt Gradual
- impaired phase 1 and phase 2 insulin release, and 3. HDL cholesterol
(1.70 mmol/L)
Family history Negative Positive
- some have impaired glucagon-like peptide 1 (GLP-1) and glucose-dependent t Men
t Women
Less than 40 mg/dL (1.03 mmol/L)
Less than 50 mg/dL (1.29 mmol/L)
Body type Thin Obese or history
of obesity
insulinotropic polypeptide (GIP) release, which further reduces the release of insulin 4. Blood pressure
5. Fasting glucose
Greater than or equal to 130/85 mm Hg
Greater than or equal to 100 mg/dL Metabolic No Often
(5.6 mmol/L)
▪ This leads to the liver’s producing and releasing glucose even in the postprandial state syndrome
Individuals having at least three of the five above criteria meet the Autoantibodies Present Rare
diagnostic criteria for metabolic syndrome.
Symptoms Polyuria, polydipsia, Asymptomatic
Kumar, Vinay., 2010, Robbins and Cotran Pathologic Basis of Disease polyphagia, rapid
weight loss
risk factors have been found to be at a much higher cardio-
Ketones at diagnosisPresent Uncommon
@AzizahVonna,MPharmSci.,Apt vascular risk than would be expected from the individual @AzizahVonna,MPharmSci.,Apt
39 components of the syndrome. Therefore, it is important to Acute Diabetic ketoacidosis Rare 40
assume a more aggressive treatment plan for each of the complications
individual abnormal components. As a result, a patient with Microvascular Rare Common
prediabetes or DM having a convergence of other risk factors complications
should be treated more aggressively than a patient having at diagnosis
prediabetes or DM alone. Macrovascular Rare Common
Diabetes Mellitus - Metabolic Syndrome Diabetes Mellitus - Metabolic Syndrome

▪ In the late 1960s, Perley and others observed that insulin’s response to oral glucose exceeded that of intravenous
(IV) glucose administration. It was concluded that factors in the gut, or incretins, affected the release of insulin after a
meal is consumed.
▪ When nutrients enter the stomach and intestines, incretin hormones are released, which stimulates insulin secretion.
▪ GLP-1 and GIP are the two major incretin hormones.
▪ Within minutes of food ingestion, GLP-1 levels rise rapidly.
▪ A glucose- dependent release of insulin occurs, and the dipeptidyl peptidase-4 (DPP-4) enzyme cleaves GLP-1 rapidly
to an inactive metabolite.
▪ Other glucose- lowering effects of GLP-1 include suppression of glucagon, slowing gastric emptying, and increasing
satiety

Kumar, Vinay., 2010, Robbins and Cotran Pathologic Basis of Disease

@AzizahVonna,MPharmSci.,Apt
41 42

Diabetes Mellitus Diabetes Mellitus

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
43 44
 Insulin Insulin Secretion
▪ Sekresi:
Vena portal → liver
Vena portal → sirkulasi perifer

▪ MOA of Insulin
Berikatan dengan reseptor pada permukaan sel
✓ memberikan efek metabolik dg segera
✓ bila berada dalam nukleus, maka efeknya
akan bersifat jangka panjang

▪ Efek:
✓ glukosa → glikogen Rang, H.P., 2012, Rang and Dale’s Pharmacology
✓ pengambilan glukosa kedalam sel
✓ FFA → trigliserida

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
45 46

Diabetes Mellitus Diabetes Mellitus

Hiperglikemia disebabkan ❖ Kompensasi dg menggunakan sumber energi lainnya, dg memetabolisme
oleh kurangnya kadar insulin ✓ protein karbohidrat
✓ lemak (TG) ketoacids
▪ glycosuria, polyuria, polydipsia ✓ lemak (TG) koma (jika tidak diatasi)
▪ sel tidak mendapatkan penghantaran
glukosa → STARVING CELL
Glycosylated haemoglobin A1c (HbA1c)
▪ Mencerminkan glukosa plasma
▪ Akan meningkat pada penderita diabetes

@AzizahVonna,MPharmSci.,Apt
47 48
 Diabetes Mellitus ~ Komplikasi Type I Diabetes
▪ Atheroma: ▪ Idiopathic, umumnya destruksi autoimmune pd sel β
Penyakit makrovaskular
Disfungsi endotelium

▪ Mikrovaskular
Kerusakan retina
Kerusakan ginjal

▪ Neuropathy:
akumulasi metabolit glukosa (sorbitol)
obat aldose reductase inhibitors tidak bermanfaat signifikan
Silbernagl,S..,2000, Color Atlas of Pathophysiology

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
49 50

Type II Diabetes Insulin Therapy

▪ Genetik dan obesitas; insulin resisten, sekresi insulin terganggu

~Insulin Endogenous~ ~Insulin Exogeneous

Silbernagl,S..,2000, Color Atlas of Pathophysiology

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
51 52
 12
BARRIERS TO INSULIN THERAPY
Insulin: Human Analog Insulin: Human Analog
Table 3.1: Barriers to insulin therapy and suggested solutions

12Possible barriers
BARRIERS TO INSULIN
Suggested THERAPY
solutions and issues for patient discussion

Insulin as a • Reassure your patient they have done nothing wrong

Table 3.1: failure
personal Barriers to insulin therapy andthe
• Emphasize suggested solutions
pathophysiology of Type 2 DM
Diabetes progression means insulin will be needed
Possible barriers eventuallysolutions and issues for patient discussion
Suggested
• Explain that starting insulin at the right time will help
12
BARRIERS TO INSULIN THERAPY Insulin as a
personal failure
• with glycemic
Reassure yourcontrol
patientandtheyslow
havedisease
• Emphasize the pathophysiology of Type 2 DM
progression
done nothing wrong

Insulin causes • Provide

Diabetesinformation
progression to means
counteract thiswill
insulin belief
be needed
complications • Acknowledging
eventually the patients fear and informing the
Table 3.1: Barriers to insulin therapy and suggested solutions and death • provider’s
Explain that experience is helpful
starting insulin at the right time will help
• Discuss that adding
with glycemic controlinsulin doesdisease
and slow not mean health is
progression
deteriorating; rather, it is an effective step to prevent
Possible barriers Suggested solutions and issues for patient discussion Insulin causes • diabetes progressiontoand
Provide information complications
counteract this belief
complications • Acknowledging the patients fear and informing the
and death
Insulin injections provider’s
• Explain theexperience
benefits ofisusinghelpful
pen / injection devices
Insulin as a • Reassure your patient they have done nothing wrong
@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
53 are painful •• Demonstrate
Discuss that adding insulin does
insulin injection not mean
technique for health is 54
personal failure • Emphasize the pathophysiology of Type 2 DM deteriorating; rather,
subcutaneous injectionsit iswith
an effective
a practicesteppentotoprevent
the
Diabetes progression means insulin will be needed diabetes Highlight
patients. progression sitesandof complications
injection
eventually • Let the patient try an injection test / placebo injection
Insulin injections • Explain the benefits of using pen / injection devices
• Explain that starting insulin at the right time will help Fear of
are painful •• Reassure
Demonstrate theminsulin
that there are strategies
injection technique to forprevent,
with glycemic control and slow disease progression hypoglycaemia recognize
subcutaneousand treat hypoglycaemia
injections and thus
with a practice pen avoid
to the
severe events
patients. Highlight sites of injection
12 •• Basal
Let theinsulins
patienthave minimal
try an risks
injection test / placebo injection
BARRIERS
Insulin causes TO information
• Provide INSULIN THERAPY
to counteract this belief
complications
Insulin: Human Analog Insulin: Human Analog
• Acknowledging the patients fear and informing the Change
Fear of in lifestyle Provide information
• Reassure them that andthere
discuss
are about insulin
strategies and pen.
to prevent,
and death 1) Restricts
hypoglycaemia • Modern
recognize injection
and treat devices (insulin pens)
hypoglycaemia andare
thus avoid
provider’s experience is helpful independence convenient, discreet and simple to use
Table 3.1: Barriers to insulin severe events
• therapy
Discuss and
that suggested solutions
adding insulin does not mean health is 2) Concern of •• Insulin can fit inhave
Basal insulins withminimal
daily liferisks
deteriorating; rather, it is an effective step to prevent injecting insulin in • Selection of insulin type and regimens with maximum
publicinplaces
Change lifestyle flexibility
Provide information and discuss about insulin and pen.
Possible barriers Suggested solutions and
diabetes progression andissues for patient discussion
complications 1) Restricts • Modern injection devices (insulin pens) are
Insulin is not
independence • Inform that diabetes
convenient, discreet isandansimple
insulin-related
to use problem
Insulin effective • and thecan
insulin
fit inused
withisdaily
verylife
similar to that produced
Insulin as a
injections •
• Reassure
Explain theyour patient
benefi ts of they
usinghave
pendone nothing
/ injection wrong
devices 2) Concern of
injecting insulin in
Insulin
• naturally
Selection of insulin type and regimens with maximum
personal
are painfulfailure •
• Emphasize the pathophysiology of
Demonstrate insulin injection technique forType 2 DM • Offer a 3-month trial to get the patient used to the idea
public places flexibility
Diabetes progression
subcutaneous means
injections withinsulin will be
a practice penneeded
to the • Once patients try insulin they rarely want to change,
eventually Insulin is not • because
Inform thatit isdiabetes
successfulis an insulin-related problem
patients. Highlight sites of injection effective and the insulin used is very similar to that produced
•
• Explain that starting
Let the patient try aninsulin at the
injection testright time will
/ placebo help
injection Insulin causes • Consult
naturallya dietician and discuss strategies to prevent
with glycemic control and slow disease progression weight gain • weight
Offer again
3-month trial to get the patient used to the idea
•• Lifestyle interventions
Once patients with
try insulin dietrarely
they and exercise continue
want to change,
Fear of • Reassure them that there are strategies to prevent, to be important
because it is successful
Insulin causes
hypoglycaemia • recognize
Provide information to counteract this
and treat hypoglycaemia andbelief
thus avoid
complications • severe
Acknowledging
events the patients fear and informing the Insulin causes • Consult a dietician and discuss strategies to prevent
and death weight gain weight gain
• provider’s experience
Basal insulins is helpful
have minimal risks @AzizahVonna,MPharmSci.,Apt • Lifestyle interventions with diet and exercise continue @AzizahVonna,MPharmSci.,Apt
• Discuss that adding insulin does not mean health is 55 to be important 56
Change in lifestyle Provide information
deteriorating; anditdiscuss
rather, about insulin
is an effective step toand pen.
prevent
1) Restricts • diabetes
Modern injection
progressiondevices
and (insulin pens) are
complications
independence convenient, discreet and simple to use
1) Restricts • Modern injection devices (insulin pens) are • Premixed insulin is biphasic insulin that incorporates the combination of
independence convenient, discreet and simple to use short or rapid-acting insulin with its intermediate-acting counterpart into a
2) Concern of • Insulin can fit in with daily life single preparation to cover for both postprandial glucose excursion as well as
injecting insulin in • Selection of insulin type and regimens with maximum basal insulin needs simultaneously (Table 4.1b).
public places flexibility

Insulin is not • Inform that diabetes is an insulin-related problem Table 4.1a Insulin Preparations available in Malaysia
effective and the insulin used is very similar to that produced
Insulin
Insulin: Human Analog
naturally
• Offer a 3-month trial to get the patient used to the idea
Type Conventional Analogue

• Once patients try insulin they rarely want to change, Prandial Short-acting regular human insulin Rapid-acting
because it is successful - Actrapid® - Novorapid® (Aspart)
- Humulin R® - Humalog® (Lispro)
Insulin causes • Consult a dietician and discuss strategies to prevent - Apidra® (Glulisine)
weight gain weight gain Basal Intermediate-acting or Neutral Long-acting
• Lifestyle interventions with diet and exercise continue Protaminated Hagedorn (NPH) - Lantus® (Glargine)
to be important Insulin - Levemir® (Detemir)
- Insulatard®
- Humulin N®

Premixed Combination of short & Combination of rapid-acting &

intermediate-acting: protaminated analogue
30% regular insulin + 70% NPH - NovoMix® 30 (30% aspart
- Mixtard® 30 + 70% aspart protamine)
- Humulin® 30/70 - Humalog Mix® 25 (25% lispro
@AzizahVonna,MPharmSci.,Apt + 75% lispro protamine)
@AzizahVonna,MPharmSci.,Apt
57 58

Insulin: Human Analog Insulin: Human Analog

Commercial insulin preparations differ in a
number of ways, such as differences in
▪the recombinant DNA production
techniques,
▪amino acid sequence,
▪concentration,
▪solubility,
▪and the time of
▪onset and duration of their biologic
action.

@AzizahVonna,MPharmSci.,Apt
@AzizahVonna,MPharmSci.,Ap
59 60
t
Insulin: Human Analog Insulin: Human Analog

@AzizahVonna,MPharmSci.,Ap @AzizahVonna,MPharmSci.,Ap
61 62
t t

Insulin: Human Analog Insulin: Human Analog

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
63 64
 Insulin Therapy Insulin Therapy
▪ Insulin, protein BM 6000 (s.c/i.v) ▪ Basal-bolus regimen ▪ Dosis,
✓ bertujuan mengontrol glukosa darah dengan cara menyerupai sekresi insulin yang o Disesuaikan dg diet dan olahraga
bervariasi pada pagi hari ✓ Depot injection at bedtime
o Tergantung dari aktivitas sel dan
✓ terjadinya komplikasi lebih lambat, tapi resiko hipoglikemia lebih tinggi ✓ Short acting insulin, diberikan setiap insulin resistance
sebelum makan terjadinya komplikasi
lebih lambat, tapi resiko hipoglikemia lebih
▪ Soluble Insulin, ▪ Depot suspension, tinggi ▪ Monitor,
o glukosa darah
o s.c → onsetnya cepat 30 menit, durasi o onsetnya lambat 2-4 jam, durasi 24-36 o HbA1c
jam o urin
5-8 jam

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
65 66

Insulin Therapy Problems T2DM Treatment

▪ Hipoglikemik ▪ Edukasi
✓ terapi intensive, meningkatkan resiko
✓ diet
✓ terlambat waktu makan
• meningkatkan makanan yg mengandung karbohidrat kompleks
✓ β-blockers (aktivasnya potensiasi thd insulin dan menutupi simptom hipoglikemik)
• mengurangi makanan dg kandungan lemak
▪ Simptom hipoglikemik
✓ meningkatkan aktivitas SSS (berkeringat, kronotropik +)
✓ olahraga
✓ Penurunan glukosa otak (lapar, sulit berfikir, tremor, pingsan)
▪ Obati dengan ▪ Jika hiperglikemik tetap tidak terkontrol, maka tambahkan terapi oral
✓ Glukosa (p.o., i.v) hipoglikemik
✓ Glukagon (i.m) o Sulfonil urea, biguanida, akarbose, glitazone, DPP4 inhibitors (liptin)

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
67 68
 Sulfonilurea Sulfonilurea
▪ Mekanisme kerja
➢ mengurangi level glukagon dalam serum
➢ stimulus pelepasan insulin dg
✓ berikatan pd tapak spesifik dari sel β (kompleks kanal KATP, reseptor sulfonilurea) menghambat
aktivitasnya
✓ Inhibisi kanal KATP menyebakan depolarisasi membran sel yang menyebabkan terbukanya kanal Ca dan
terjadinya sekresi insulin

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
69 70

Sulfonilurea Sulfonilurea
▪ Mekanisme kerja ▪ Adverse effects
➢ Mechanism: stimulate insulin release from binding to sulfonlyurea o Hipoglikemik
B-cell site. – terutama agen yang bersifat long-acting,dan pemakaian pada pasien lanjut usia, pasien dg
gangguan CV/hepar/renal
➢Target post-prandial glucose.
➢ Place in therapy: monotherapy, combination therapy, can be first o Menstimulus selera makan → BB bertambah
line.
o Interaksi Obat, resiko yg paling berbahaya adalah hipoglikemik
➢Reduction in HbA1c: 0.9–2.5%.
– NSAID, diuretic, β-blocker
➢ Risks: hypoglycaemia, weight gain.

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
71 72
 Biguanida Biguanida
The only member of the biguanide ▪ Penggunaan
class available for use today o Pasien NIDDM yg obesitas (1st line)
No effect on insulin release

▪ Adverse effects
▪ Mekanisme kerja, (belum sepenuhnya jelas) o Paling umum GI, (anoreksia, diare, nause)
Jalur utama
✓ Mengurangi produksi glukosa hepatik melalui aktivasi enzim AMPK (jalur utama) o Asidosis laktat
Jalur lainnya – jarang tapi serius
✓ ↓ glukoneogenesis, ✓ ↓ glukosa darah (independen thd sel β), – resiko bertambah pada pasien gagal ginjal, gagal jantung, ke rusakan liver
✓ ↑ glikolisis ✓ mencegah hiperglikemia (setelah makan)
✓ ↓ absorbsi glukosa dari GIT
✓ tidak menyebabkan hipoglikemi atau menambah selera ❖ kontraindikasi bila ClCr , 30 ml/min
✓ ↓ glukagon makan
✓ ↓ LDL, VLDL

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
73 74

Biguanida Biguanida
▪Mechanism: decrease gluconeogenesis and increase peripheral utilization of ▪ Maximum effective dose is 2000mg/day.
glucose. ▪ Lactic acidosis rare (<0.3%, but 50% fatal), does not cause hypoglycaemia.
▪Target fasting blood glucose. ▪ Contraindicated with serum creatinine 133µmol/L in men and 124µmol/L in women.
▪Place in therapy: considered first line, monotherapy, combination 
 ▪ Use with caution in patients aged >80 years (should have normal renal clearance) and
therapy. in those with hepatic dysfunction, alcoholism, unstable congestive heart failure (CHF),
▪ Reduction in HbA : 1–1.3%.
1c
or dehydration.

▪ Available as metformin immediate release and metformin extended 
 ▪ GI side effects (nausea, vomiting, diarrhoea) occur in up to 50% of patients; can give
release (MR); no real advantage over standard formulation. 
 with food; start low and go slow.
▪ Improved lipid profile; weight neutral or weight loss.
▪ Decreased macrovascular events.

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
75 76
 α glucosidase inhibitors Meglitinides

Acarbose ▪ Stimulate more insulin

▪ Mekanisme kerja production ; dependant - Prandin ® O

✓ Menghambat absorpsi glukosa dengan cara menghambat scr kompetitif α-glucosidase (repaglinide)
upon level of glucose
N O OH

(terlibat dalam metabolisme karbohidrat) NH O

❖ ↓ hiperglikemia postprandial present 2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid

▪ a benzoic acid derivative

- Starlix ®
and a short-acting insulin
NH

▪ Adverse effects (nateglinide) O OH

O

✓ Flatulen, diare releaser. 2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
77 78

Meglitinides Meglitinides
▪ Mekanisme kerja ▪ Mekanisme kerja
➢ It stimulates the release of insulin from ➢ Mechanism: stimulate insulin release from binding to sulfonlyurea B-cell site.
the pancreatic beta cells by closing ATP-
➢Target post-prandial glucose; short-acting.
sensitive potassium channels. (Closes KATP
➢Place in therapy: monotherapy or combination therapy.
channels on β-cell plasma membranes)
➢ Accentuated effects around meal ingestion ➢Reduction in HbA1c: 0.6–0.8%.
➢ Rapid onset and short duration of action ➢Examples: repaglinide, nateglinide.
make multiple daily doses necessary (take ➢ Risks: hypoglycaemia; weight gain.
it immediately before each meal!). ➢ The need for frequent dosing may adversely affect compliance. 


@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
79 80
 Thiazolidinedion Thiazolidinedion
Pioglitazone, Rosiglitazone Pioglitazone, Rosiglitazone
▪ Mekanisme kerja ▪ Mekanisme kerja
o ↑ respon jaringan terhadap insulin o ↑ respon jaringan terhadap insulin
o make cells more sensitive to insulin (esp. fatty cells)
▪ Adverse effects
o Cardiovascular safety?? N O
O

Pioglitazone NH

- Actos®, Avandia® O
5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
81 82

Thiazolidinedion Thiazolidinedion
Pioglitazone, Rosiglitazone
▪ PPARγ is a member of the steroid hormone nuclear receptor superfamily,
and is found in adipose tissue, cardiac and skeletal muscle, liver and
placenta
▪ Upon activation of this nuclear receptor by a ligand such as a TZD, PPARγ–
ligand complex binds to a specific region of DNA and thereby regulates the
transcription of many genes involved in glucose and fatty acid metabolism.

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
83 84
 Thiazolidinedion
Pioglitazone, Rosiglitazone
▪ Target fasting blood glucose.
▪ Place in therapy: considered second line, but could be monotherapy in patients with
lower HbA range(6.5–8%), combination therapy. Reduction in HbA : 1.5–1.6%.
1c 1c

▪ Oedema and weight gain occur more in combination with insulin.

▪ Contraindicated in NYHA Class III and IV heart failure; do not use in patients with
underlying liver dysfunction.
▪ Delayed onset of action; may be 6–8wks (or as much as 12wks).
▪ Pioglitazone may have positive effects on lipids (iHDL, dTG).

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
85 86

Glucagon-Like Polypeptide-1 (GLP-1) Receptor Glucagon-Like Polypeptide-1 (GLP-1)

Agonist Receptor Agonist
Exenatide ▪ Glucagon-like peptide-1 (GLP-1) incretin mimetic; mimics incretin hormone given by
injection.
▪ Mechanism: stimulates insulin secretion in response to glucose load; inhibits release of
glucagon following a meal; increases satiety; slows absorption of nutrients through delayed
gastric emptying.
▪ Place in therapy: adjunct therapy for use in combination with sulfonyl- ureas, metformin,
or a combination of these.
▪ Reduction in HbA : 0.8–0.9%.
1c

▪ Common side effects include nausea and vomiting (dose-related).

▪ Recent reports of possible exenatide pancreatitis have arisen.

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
87 88
 Glucagon-Like Polypeptide-1 (GLP-1)
NIDDM ~ Dipeptidyl peptidase-4 (DPP-4) inhibitors
Receptor Agonist
Vildaliptin, Sitagliptin, Saxaliptin, Slogliptin ▪ Mechanism: slows inactivation of incretin hormone GLP-4, suppressing
glucagon secretion and increasing glucose-dependent insulin release.
▪ Target post-prandial blood glucose.
▪ Place in therapy: monotherapy or combination therapy.
▪ Reduction in HbA : 0.8%.
1c

▪ Dosage adjustment necessary in renal dysfunction.

▪ Delay gastric emptying, Increase satiety.
▪ Weight neutral.

@AzizahVonna,MPharmSci.,Apt @AzizahVonna,MPharmSci.,Apt
89 90

end of lectures...

@AzizahVonna,MPharmSci.,Apt
91