Tim Dosen Bidang Farmasi Klinik

PROGRAM STUDI FARMASI

FAKULTAS KEDOKTERAN UNIVERSITAS BRAWIJAYA
 Introduction

 Type 2 DM  the most prevalent form of diabetes
(90% to 95% of all diagnosed cases)
 Slow and progressive development, often preceded
by pre-diabetes (individual at high risk of eventually
developing diabetes)
 Rising blood glucose levels result from increasing
insulin resistance & impaired insulin secretion
 The complications  one of the leading cause of
death in the world & need high annual health care
cost
 Definition

Diabetes Mellitus is a group of chronic metabolic
disorders characterized by hyperglycemia that may
result in long-term microvascular, macrovascular,
and neuropathic complications
Objectives

DM populations with Least
appropriate medications complications

DM populations with
medications

Most
DM populations complications
Type 2 DM Characteristics

relative
insulin
deficiency

Type 2
DM
insulin
resistance
Type 2 diabetes Major Risk

Genetic

First degree family history of DM

Overweight or obese

Habitual physical inactivity

Previously identified with pre-diabetes

Hyperlipidemia

History of gestational diabetes or delivery of greater than 4.09 kg babies

How to Differentiate between
type 1 & type 2 DM?

Below than 1 ng/mL Type 1
DM

Greater than 1 ng/mL Type 2

DM
 Medications That May Affect
Glycemic Control

Drug Effect on Glucose Mechanism
ACE inhibitors Slight reduction Improves insulin sensitivity
Alcohol Reduction Reduces hepatic glucose
production
Diuretics Increase May increase insulin resistance
Phenytoin Increase Decreases insulin secretion
Sympathomimetics Slight increase Increased glycogenolysis and
gluconeogenesis
Glucocorticoids Increase Impairs insulin action
β-blockers May increase Decreases insulin secretion
This list is not inclusive of all medications reported to cause glucose changes
 The Fate of Glucose

 ATP production
 Amino acid synthesis
 Glycogen synthesis
 Triglyceride synthesis
Normal Glucose Metabolism

Glucose Catabolisms

Glucose, Triglycerides & Ketogenesis

Glucose, Protein, & Ketogenesis

 Typical Clinical Presentation of DM

Characteristic Type 1 DM Type 2 DM
Age of onset Childhood/adolescence Above 40 years of age
Speed of onset Abrupt Gradual
Family history Negative Positive
Body type Thin Obese or history of obese
Metabolic syndrome Rare Often
Autoantibodies Present Rare
Symptoms Polyuria, polydipsia, Asymptomatic
polyphagia, rapid weight loss
Ketones at diagnosis Present Uncommon
Acute complications DKA Rare
Microvascular & Rare Common
macrovascular complications
 Criteria of Diabetes Diagnosis
(Laboratory Parameters)

1 A1C > 6.5%. The test should be performed in a laboratory using a
method that is NGSP certified and standardized to the DCCT assay

2 FPG > 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for
at least 8 h

2-hour plasma glucose > 200 mg/dl (11.1 mmol/l) during an OGTT.

3 The test should be performed as described by the World Health

Organization, using a glucose load containing the equivalent of 75 g
anhydrous glucose dissolved in water

4 In a patient with classic symptoms of hyperglycemia or hyperglycemic

crisis, a random plasma glucose 200 mg/dl (11.1 mmol/l)

In the absence of unequivocal hyperglycemia, criteria 1–3 should be

confirmed by repeat testing
 Categorization of Glucose Status

Fasting Plasma Glucose


mg/dL mmol/L

(FPG):
Normal < 100 < 5.6

Impaired Fasting Glucose 100-125 5.6-6.9

(IFG)
DM ≥ 126 ≥ 7.0

2-Hour Postload Plasma

Glucose (Oral glucose
tolerance test):
Normal < 140 < 7.8

Impaired Glucose Tolerance 140-199 7.8-11.0

(IGT)
DM ≥ 200 11.1
Correlation of A1C with average
glucose

 Complications
•
•
 The Eye: Diabetic Retinopathy/Ophthalmopathy
The Kidney: Diabetic Nephropathy
Microvascular
• Diabetic Peripheral and Autonomic Neuropathy
complications
• The Diabetic Foot Ulcer
• Cutaneous Complications of Type 1 Diabetes

Changes in the arteries (hyperglycaemia induce

Macrovascular
atherogenesis, hypertension, down-regulation of the
complications
anticoagulant thrombomodulin)

• Infection and Diabetes

• Pancreas Transplantation
Other
• Islet Transplantation
complications • β-Cell Replacement Therapy for Type 1 Diabetes
• Islet Growth Factors
Goals of Therapy
 reducing long-
term
microvascular
complications

maintaining Reducing
the patient’s longterm
overall quality macrovascular
of life complications
DM treatment
goals

preventing
acute
minimizing
complications
hypoglycemic
from high
episodes
blood glucose
levels
 ADA Recommended Goals of Therapy
Parameter Goals

Glycemia:

HbA1c

< 7% (every 3 months if above, 6 months if below)

Preprandial plasma glucose 90-130 mg/dL (every 3 years in adults over 45 years of age, more
frequent in individuals with additional risk factors)
Peak postprandial plasma glucose < 180 mg/dL

Blood pressure: < 140/90 mmHg (evaluate at every visit)

Lipids:

LDL < 100 mg/dL or < 70 mg/dL if high risk

HDL > 40 mg/dL or > 50 mg/dL

TG < 150 mg/dL

Monitoring for compications:

Eyes Dilated eye exam (yearly)

Feet Feet (should be examined at every visit)

Urinary microalbumin yearly

Type 2 DM Glycemic Control Algorithm


 Guideline According to the
Hb1c Levels

 6.5–7.5% - Monotherapy
 7.6–9% - Dual therapy
 Greater than 9%- Insulin (if symptomatic or under
treatment) or triple therapy (if asymptomatic)
Comparison of T2DM Drug
Therapy Recommendations


 Oral Agents for DM
Pharmacologic Therapy

Insulin •Sulfonylurea (Glipizide, Glimepiride, Glibenclamide)
•Non-sulfonylurea secretagogues (Nateglinide,
secretagogues Repaglinide)

Insulin •Thiazolidinediones (Pioglitazone, Rosiglitazone)

•Biguanides (Metformin)
sensitizers •DPP-IV inhibitors (Sitagliptin)

•Acarbose
Others •Miglitol
S 100, 250 mg
(once daily) 
effect up to 72 h
u Chlorpropamide
caution in
l elderly and
kidney disease

f 1st generation
250, 500 mg (2-
3/day)  effect
o Tolbutamide
up to 12 h

n useful in kidney
disease
i 5, 10 mg (1-
l 2/day)  effect
up to 20 h

u Glipizid

empty stomach
r 2nd generation
e 1,2,4 mg (once
daily)  effect
up to 24 h
a Glimepiride

s take with first

main meal
 Sulfonylureas Mechanism of Action

 Peningkatan sekresi insulin.
 Sulfonilurea mengikat reseptor sulfonilurea spesifik
pada sel β pankreas  ikatan tsb menutup saluran
K+ yg tergantung ATP  penurunan keluaran K+ 
depolarisasi membran  saluran Ca2+ terbuka 
Ca2+ masuk  peningkatan jumlah Ca2+
intraseluler  insulin dikeluarkan.
Sulfonilurea Considerations

 Insulin secretagogues that stimulate insulin release
from pancreatic beta cells
 May also enhance peripheral sensitivity to insulin
 Hypoglycemia is the most common side effect
Non-Sulfonylurea Secretagogues

0.5,1,2 mg (3
times/day)  effect
up to 4 h
Repaglinide
Frequency of dosing
dependent on
frequency of meals

60, 120 mg (3
times/day)  effect
up to 4
Nateglinide
Frequency of dosing
dependent on
frequency of meals
Meglitinide Considerations

 Shorter-acting insulin secretagogues than the
sulfonylureas
 Preprandial dosing potentially achieving more
physiologic insulin release
 Less risk for hypoglycemia
 Can be used as monotherapy
 If adequate glycemic control is not achieved  metformin
or thiazolidinedione may be added
 May be used in patients who have allergy to sulfonylurea
 Have a similar risk for inducing weight gain as
sulfonylureas
Non-Sulfonylurea Secretagogues
Mechanism of Action

Mechanism:
Similar to sulfonylureas with some overlap in binding
sites
Effect:
 In patients with functioning beta cells
 Reduces circulating glucose, increases glycogen, fat,
and protein formation
 Gene regulation
 Biguanides

500, 850, 1000 mg (2-3
times daily)  effect
up to 24 h
Metformin
Discontinue if serum
creatinine greater than
1.4 mg/dL (females)
or 1.5 mg/dL (males)

Diminum bersama makanan untuk mengurangi ES

pada saluran cerna
Metformin Mechanism of Action

 Metformin meningkatkan sensitivitas insulin pada lever dan
jaringan perifer  terjadi peningkatan masukan glukosa pada
jaringan perifer.
 Mekanisme pasti bagaimana metformin meningkatkan
sensitivitas insulin  sedang diteliti.
 Metformin tidak punya efek langsung pada sel β pankreas,
meskipun kadar insulin menurun.
 Efek utama metformin adalah dengan menurunkan produksi
glukosa hepatik melalui aktivasi enzim AMP-activated protein
kinase dan meningkatkan stimulasi ambilan glukosa oleh otot
rangka dan jaringan lemak.
 Metformin Considerations

 Metformin rarely causes hypoglycemia
 Metformin is the only oral diabetes drug that reliably
facilitates modest weight loss
Thiazolidinediones

15,30,45 mg (once daily)
 effect 24 h

Pioglitazone
Metabolism by
cytochrome P-450 2C8
and 3A4 pathways, days
for onset of action

2,4,8 mg (1-2/day) 
effect up to 24 h

Rosiglitazone
Metabolism by
cytochrome P-450 2C8
and 3A4 pathways, days
for onset of action
 Thiazolidinediones Mechanism
of Action

Mechanism:
Regulates gene expression by binding to PPAR-γ and
PPAR-α
Effect:
Reduces insulin resistance
 Thiazolidinediones Considerations

 Act as insulin sensitizers  require the presence of
insulin to work
 Must be taken for 12-16 weeks to achieve maximal effect
 Used as monotherapy or in combination with
sulfonylurea, metformin, meglitinide, DPP-4 inhibitors,
GLP-1 receptor agonists, or insulin
 Generally decrease triglyceride levels and increase HDL
cholesterol levels, though increase LDL cholesterol
 Weight gain may be problematic adverse effects
 Fluid retention from TZDs has been considered resistant
to treatment with loop diuretics, because of upregulation
of renal epithelial sodium channels
α-Glucosidase Inhibitors

25,50,100 mg (1-3
times/day)  effect
up to 3 h
Acarbose
Eliminated in bile,
take with first bite of
meal, little absorption

25,50,100 mg (1-3
times/day)  effect
up to 3 h
Miglitol
Eliminated through
kidney and feces, take
with first bite of meal
 α-Glucosidase Inhibitors
Mechanism of Action

Mechanism:
Inhibit intestinal α-glucosidases
Effect:
 Reduce conversion of starch and disaccharides to
monosaccharides.
 Reduce postprandial hyperglycemia
 α-Glucosidase Inhibitors
Considerations

 Induction of flatulence greatly limits their use
 Should be titrated slowly to reduce gastrointestinal
(GI) intolerance
DPP-4 Inhibitor, Incretin Mimetics, &
Amylin Analogue
 25,50,100 (once
daily)  effect 24
h
Sitagliptin
Reduce dosage for
DPP-4 Inhibitor
renal insufficiency
Vildagliptin

Exenatide
Incretin Mimetics
(GLP-1 Analogue)
Liraglutide

Amylin Analogue Pramlintide

DPP-4 Inhibitor Mechanism of Action


DPP-4 Inhibitor, Incretin Mimetics, & Amylin Analogue
Mechanism of Action
Comparison of Incretin-Based Therapies
 GLP-1 Analogue
Considerations

 The addition of exenatide in patients receiving
insulin glargine as basal insulin helps to improve
glycemic control without the risk of increased
hypoglycemia or weight gain
 Although the original product requires twice-daily
injections, a long-acting exenatide formulation that is
given once weekly
 Dipeptidyl Peptidase IV
Inhibitors Considerations

 Can be used as a monotherapy or in combination
with metformin or a TZD
 They are given once daily
 Amylin Analogue
Considerations

 Delays gastric emptying
 Decreases postprandial glucagon release
 Modulates appetite
 Other Medications

 Bile acid sequestrants  colesevelam  adjunctive
therapy to improve glycemic control, but
insignificant impact on FPG and HbA1c levels
 Dopamine agonists  bromocriptine given in a
single timed morning dose  act on circadian
neuronal activities within the hypothalamus to reset
the abnormally elevated drive for increased plasma
glucose, triglyceride, and free fatty acid levels in
fasting and postprandial states in insulin-resistant
patients
 Combination Products

• 1.25/250 & 2.5/500 mg
Glyburide/metformin
• Twice daily with meals

• 2.5/250 & 2.5/500 mg

Glipizide/Metformin
• Twice daily with meals

• 1/500-1000; 2/500-1000 & 4/500-1000 mg

Rosiglitazone/Metformin
• Twice daily with meals

• 15/500 & 15/850 mg

Pioglitazone/Metformin
• 1-2/day
Comparison of Therapies for T2DM
Hyperglycemia Added to Metformin


 Insulin

Rapid-acting insulin  rapid onset, short duration of action (Lispro,
Aspart, Glulisine)

Short-acting insulin (reguler)  OOA: 30-45 mnts, peak after 1-2 h

(Humulin R)

Intermediate duration delayed onset of action, extended duration

of action (Humulin N)

Long-acting insulin  do not produce peak serum concentrations

(Glargine, Detemir)

Oral inhalation insulin  alternative to mealtime injectible insulin, OOA

10-20 mnts, DOA 6 h (Exubera)
Insulin Extent & Duration of Action

Patients Care & Monitoring

Assess the patient for development or progression of DM and DM-related
complications

Evaluate Glucose level

Assess the patient for changes in quality-of-life measures

Perform a thorough medication history of prescription, over-the-counter, and

herbal product use

Review all available laboratory data to evaluate therapy goals

Recommend appropriate therapy, and develop a plan to assess effectiveness

Stress adherence to prescribed lifestyle and medication regimen

Provide patient education on diabetes, lifestyle modifications, appropriate

monitoring, and drug therapy
 GESTATIONAL DIABETES MELLITUS
(GDM)


 Gestational diabetes mellitus (GDM) is defined as any
degree of glucose intolerance with onset or first
recognition during pregnancy.
 The definition applies whether insulin or only diet
modification is used for treatment and whether or not the
condition persists after pregnancy.
 Approximately 7% of all pregnancies are complicated by
GDM, resulting in more than 200,000 cases annually.
 Detection and Diagnosis of GDM


 Risk assessment for GDM should be undertaken at the
first prenatal visit.
 Women with clinical characteristics consistent with a high
risk of GDM (marked obesity, personal history of GDM,
glycosuria, or a strong family history of diabetes) should
undergo glucose testing as soon as feasible.
 If they are found not to have GDM at that initial
screening, they should be retested between 24 and 28
weeks of gestation.
 Women of average risk should have testing undertaken at
24–28 weeks of gestation.
 Detection and Diagnosis of GDM
Continue……..


 Low-risk status requires no glucose testing, but this
category is limited to those women meeting all of the
following characteristics:
Age <25 years No known diabetes in first-degree
relatives
Weight normal before pregnancy No history of abnormal glucose
tolerance
Member of an ethnic group with a No history of poor obstetric
low prevalence of GDM outcome

A fasting plasma glucose level >126 mg/dl (7.0 mmol/l) or a casual

plasma glucose >200 mg/dl (11.1 mmol/l) meets the threshold for the
diagnosis of diabetes.
PATHOPHYSIOLOGY OF GDM


 Management for GDM


 Medical Nutrition Therapy

 There is evidence that effective treatment that leads to normalization of maternal

glucose concentrations results in a better pregnancy outcome.
 The cornerstones of GDM treatment are lifestyle modifications (medical nutrition
therapy, physical exercise, cessation of smoking) and insulin administration.

Oral Hypoglycemic Agents
Glibenclamide
 Glibenclamide most probably
does not cross the placenta.
 Its use during pregnancy has
not been associated with
neonatal hypoglycemia or
increase in congenital
anomalies.
 According to data from
randomized control trials
(RCTs), glibenclamide is
comparable to insulin in terms
of effectiveness, though
an increase in macrosomia has
been reported.
Management for GDM
Metformin
 Metformin readily crosses the placenta.
 Nevertheless, its use during pregnancy has not
been associated with an increase in congenital
anomalies.
 According to data from RCTs, metformin is
comparable to insulin in terms of effectiveness,
though in 50% of cases insulin has to be added.
 A possible indication for metformin use during
the first trimester of pregnancy could be the
prevention of GDM in women with polycystic
ovary syndrome (PCOs)  However, a recent
study failed to show such an effect.
 A recent meta-analysis concluded that the
existing evidence supports the efficacy and safety
of metformin during pregnancy with respect to
pregnancy outcomes.
 Management for GDM
INSULIN


 Insulin treatment remains the cornerstone of GDM
treatment.
 The main clinical questions are the same, as in any other
case of insulin usage:

When (must insulin be started)?

Which (type of insulin needs to be used)?
How (will insulin be administered: regimen, dosage)?
What (are the therapeutic targets)?
 Management for GDM
INSULIN Continued …….


 Τhe follow-up parameters that need to be taken into consideration for insulin
initiation in a woman whose pregnancy has been complicated by GDM are
both metabolic (HBGM, CGM, HbA1c, body weight) and ultrasonographic
(EFW, HC, AC, Fl, polyhydramnios).
 The rapid-acting insulin analogues lispro and aspart, like any other type of
insulin, do not cross the placenta.
 There is no evidence of increased risk for congenital anomalies or antibody
production.
 They both comprise safe therapeutic options, with similar efficacy, in terms of
metabolic control and number of hypoglycemic episodes.
 An intermediate-acting insulin [neutral protamine Hagedorn (NPH) or
analogue] before bed is an obvious option for fasting hyperglycemia, whereas
a rapid- or ultra-rapid-acting insulin before a specific meal has to be
considered to deal with post-prandial hyperglycemia.
 Primary Refferences

 Standard of Medical Care in Diabetes. 2011.
American Diabetes Association.
 Scobie, I.N., 2007. Atlas of Diabetes Mellitus. 3rd Ed.
Informa Health Care. UK
 Watkins et al. 2003. Diabetes and Its Managements.
6th Ed. Blackwell Publishing. London
 Mogensen, C.E., 2007. Pharmacotherapy of Diabetes:
New Developments Improving Life and Prognosis
for Diabetic Patients. Springer. Denmark.
THANK YOU