ANTIDIABETIC DRUGS

DEFINITION
Diabetes mellitus is defined
as an elevated blood
glucose associated with
absent or inadequate
pancreatic insulin secretion
with or without concurrent
impairment of insulin
action (Katzung B.G., 2009; WHO 2014)
 Classification

Type 1 diabetes Type 2 diabetes

Pancreas fails to the body's inability to

produce the insulin respond properly to
which is essential for the action of insulin
survival. produced by the
pancreas.
Environmental fc
Lifestyle changes Genetic Factors
High fat/lack of exercise
Interaction
Obesity

Insulin resistance Decreased insulin seretion

Relative insufficiency of insulin action

Development of type 2 diabetes

 Factors causing increase in visceral fat
1 Stress-related factors
-overeating, especially excessive intake of simple sugars

-smoking
-Increase in alkohol intake
-disorders of nervous and endocrine systems:increase in cortisol,
abnormality in sex hormone secretion

2 Lowered energy consumption due to a lack of exercise

3 Genetic factors
4 Aging
 PREDIABETES
Reflects failing pancreatic compensation to an underlying
state of insulin resistance (caused by obesity)

Current criteria: impaired glucose tolerance, impaired fasting

glucose, or metabolic syndrome  a 5-fold increase in future
T2DM risk

The primary goal management : WEIGHT LOSS

 PREDIABETES
Antihyperglycemic medications :
Metformin and acarbose

Reduce the risk of future DM in prediabetic patients by 25 to 30%

Well tolerated AND safe
CV benefits
(Chiasson J.L., et al.1994; Gerstein H.C., et al.2006)

Prevented future DM in 60 to 70 % of subjects with

Thiazolidinediones prediabetes,but have a number of AEs
 PHARMACOTHERAPY

Achieving the glucose target and hemoglobin AIC goal

AIC ≤ 6,5% for most patients

AIC > 6,5 % if the lower target cannot achieved without AEs
In large clinical trialintensive gluc-lowering th/ (target AIC < 6% in
pt with baseline AIC >8,5% was associated with increased mortality
in older and middle-aged patients with longstanding diabetes who
were at high risk CVD

In other trial : higher AIC target for intensively treated pt  no-

between –group diff in CVD endpoints, CV deaths, or overall death.
(Duckworth W., et al. 2009 ; Gerstein H.C., et al. 2008)
 Pharmacotherapy 2
• Patients with recent-onset T2DM or mild
hyperglycemia (AIC < 7,5%) TLC with
monotherapy :

Metformin
Alternatives: GLP-I agonists, ipeptidyl-
peptidase-4 (DPP-4) inhibitors, and alpha-
glucoside inhibitors (AGIs)
TZD, Sulfonylureas (SFUs) and glinides may also be used  but
should be used with caution owing to the potential for weight gain,
hypoglicemia, or other risk
 Treatment
The mainstay of non-pharmacological
diabetes treatment is diet and physical
activity.

About 40% of diabetes sufferers require

oral agents for satisfactory blood glucose
control, and some 40% need insulin
injections.

People with Type 1 diabetes are usually

totally dependent on insulin injections for
survival

The majority of people suffering from

diabetes have the Type 2 form.
An algorithm for the treatment of type 2 diabetes mellitus
Subclass drugs used for Diabetes
INSULIN

SULFONYLUREAS

Meglitinides

BIGUANIDES

ALPHA-GLUCOSIDASE
INHIBITORS

THIAZOLIDINEDIONES
 Lowering blood glucose by
Have been used for
stimulating insulin secretion
treatment T2DM for nearly
from the β cells of the
50 years
pancreatic islets

SULPHONYLUREAs

The drugs bind to the β-cell

sulphonylurea receptor
When sulphonylureas
(SUR)-1 closes K-ATP
interact with SUR1release
CHANNELS)reduces
of pre-formed insulin
cellular potassium efflux
granules adjacent to the
depolaritationopening
plasma membranc(“first
voltage-dependent Ca
phase” of insulin release)
channels influx of Ca
release insulin
 Sulphonylureas
2 additional mechanisms of action have been
proposed:
1. A reduction of serum glucagon levels
Mechanisme is unclear
Appears to involve indirect inhibition due to
enhanced release both insulin and
somatostatin which inhibit alpha-cell secretion
2. Closure of potassium channels in
extrapancreatic tissue
Farmakokinetika golongan sulfonilurea
 First –Generation Sulphonylurea
Chlorpropamide a Tolazamide has a
half-life of 32 hours
shorter duration of
and is slowly
Tolbutamid metabolized in the action. More slowly
liver to products thatabsorbed than the
well absorbed. retain some biology other
Rapidly activity. sulphonylureas.
metabolized in the 20-30% is excreted Half-life is 7 hours.
liver. unchanged in the It is metabolized to
Its duration of urine. several compunds
effect is short. Dosage higher than that retain
500 mg/d  increase hypoglicemic
Elimination half-life
jaundice effects. If more than
of 4-5 hours
Maintenance dosage : 500 mg/d are
250 mg/d, SD in the require divided
morning and given 2 daily
 Second Generation
Sulfonylurea

Glyburide Glipizide Glimepiride

 GLYBURIDE
Metabolized : Hepar  into products
with very low hypoglycemia activity

Usual starting dosage: 2,5 mg/d or less

Average maintenance :dosage : 5-10

mg/d, single morning dose

Maintenance > 20 mg/d not

recommended

A formulation “micronized” glyburide is

available in a variety of tablet sizes
 Glyburide

FDA recommends careful

monitoring to retitrate Few Aes, potential for
dosage when switching causing hypoglicemia
from standart doses or from
1 other sulfonylurea drugs 2

3 4
Flushing has rarely been Contraindication :
reported after ethanol hepatic impairment
ingestion and renal
insufficiency
Glipizide

Has the shorted half-life :2-4 hours

Ingestion : 30 minutes before breakfast absorption is

delayed by food

Recommended starting dosage : 5 mg/d – 15 mg/d SD

Higher dosage  should be divided, given before meals

Total daily dosage recommended by the manufacturer : 40

mg/d
Glipizide

90% of glipizide :
metabolized in the liver to
inactive products

10% is excreted unchanged

in the urine

Contraindication: hepatic or
renal impairment
 GLIMEPIRIDE
• Once daily use as monotherapy or combination
with insulin
• A single daily dose of 1 mg has been shown to be
effective
• The recommended maximal daily dose :8 mg
• Has a long duration of effect with a half-life of 5
hours
• It is completely metabolized by the liver to inactive
product
 Meglitinides

• Repaglinide
– a new non-sulfonylurea insulin secretagogue
agent, the first available from the meglitinide
class.
• Nateglinide
– the newest member of the class, has recently
become available
 The first member of
the meglinitides
Very fast onset, a
peak Modulate beta-
concentration and cell insulin release
peak effect : 1 by regulating
Meglitinide :
hour after potassium efflux
Repaglinide
ingestion, through the
duration : 5-8 potassium
hours channels
Have 2 binding sites
in common with
sulfonylurea and one
uniqe binding site
 Repaglinide
• It is hepatically cleared by CYP3A4
• Plasma half-life: 1 hour
• Onset : rapid  controlling glucose excursion
• Should be taken before each meal in doses of 0,25 mg –
4 mg (maximum 16 mg/d)
• If the meal contains inadequate CH  hypoglycemia
• Caution : renal and hepar impairment
• Is approved as monotherapy or its combination with
biguanides
• There is no sulfur in structure  can be used by T2DM
with sulfur or sulfonylurea allergy
 Nateglinide
• Stimulates very rapid and transient release of
insulin from beta-cells through closure of the
ATP sensitive K+ channel.
• Ingestion : just before meal
• Absorption : 20 minutes
• Metabolism : hepar, by CYP2C9 and CYP3A4
• A half-life of 1,5 hours
• The overall duration of action : < 4 hours
 BIGUANIDES
AN ANTIHYPERGLYCEMIC AGENT
 its lowers blood glucose
concentration in t2d without
causing overt hypoglicemia
Metformin
Increases plasma levels of
glucagon-like peptide 1 (GLP-1)
and induces islet incretin receptor
gene expression through a
mechanism that is dependent on
PPAR-α(Maida et al)
INSULIN SENSITIZER reduces
insulin resistance and significant
reduction of plasma fasting
insulin level
Primary function : decrease
hepatic glucose production,
mainly by inhibiting
gluconeogenesis.
 BIGUANIDE-METFORMIN
• Accumulation of metformin in the liver has been shown
to be higher than in other tissues, reaching hundreds of
μM in the periportal area (Wilcock C, et al. 1994)

• Deletion of the OCT1 gene in mouse dramatically

reduces metformin uptake in hepatocytes and human
individuals carrying polymorphisms of the gene
(SLC22A1) display an impaired effect of metformin in
lowering blood glucose levels (Shu Y, et al.2007)
 BIGUANIDE-METFORMIN
• The activation of AMP-activated protein kinase (AMPK)
was intimately associated with the pleiotropic actions
of metformin ( Zhou g., et al.2001)
• AMPK is a heterotrimeric protein consisting of a
catalytic α-subunit and two regulatory subunits β and γ
and each subunit has at least two isoforms.
• AMPK is activated by increase in the intracellular AMP-
on-ATP ratio resulting from imbalance between ATP
production and consumption.
 BIGUANIDE-METFORMIN
• Metformin most likely does not directly activate
either LKB1 or AMPK as the drug does not influence
the phosphorylation of AMPK by LKB1 in cell-free
assay (Hardie D.G. 2006)
• There is evidence that AMPK activation by metformin
is secondary to its effect on the mitochondria, the
primary target of the drug.
 BIGUANIDS-METFORMIN
• First line therapy for T2DM
• Does not increase weight or provoke
hypoglicemia
• Decreases the risk of macrovascular and
microvascular disease
• Also indicated for use in combination with
insulin secretagogues or thiazolidinediones in
T2DM in whom oral monoth/ is inadequate
 BIGUANIDS-METFORMIN
• Eficacy: prevent the new onset T2DM in middle-aged,
obese person with impaired glucose tolerance and fasting
hyperglicemia
• did not prevent diabetes in older, leaner prediabetics (the
landmark Diabetes Prevention Program)
• the dosage : 500 mg – 2,55 g/daily
• Can be initiated as a once-daily dose a bedtime or before a
meal.
• common schedule : fasting hyperglycemia  begin with a
single 500 mg tablet
• If tolerated wo/ GI dicomfort and hyperglicemia persist, a
second 500 mg tablet  added to be taken with breakfast
or the midday meal or the larger (850 mg) tablet 2 daily
 BIGUANIDES-METFORMIN
• Most common toxic effects : GI (anorexia,
nausea, vomiting, abdominal discomfort, and
diarrhea)  occurs in up to 20% pt
• Dose related
• Occur at the onset of therapy
• Persistent diarrhea stop (3-5% pt)
• CI  renal disease, alcoholism, hepatic disease,
conditions predisposing to tissue anoxia coz of
an increased risk of lactid acidosis induced by
biguanide drugs
THIAZOLIDINEDIONES
 THIAZOLIDINEDIONES

• Rosiglitazone
• Pioglitazone
 Combination preparations are also available
 THIAZOLIDINEDIONES
The principal mechanism

Stimulation of PPAR-γ enhance insulin

sensitivity
PPAR-γ is expressed at highest
levells in adipose tissue, and less
so in muscle and liver
 THIAZOLIDINEDIONES
• ACTOS is a thiazolidinedione antidiabetic
agent that depends on the presence of insulin
for its mechanism of action.
• ACTOS decreases insulin resistance in the
periphery and in the liver resulting in
increased insulin-dependent glucose disposal
and decreased hepatic glucose output.
THIAZOLIDINEDIONES
Action of Pioglitazone in a Diabetic Patient
 THIAZOLIDINEDIONES

• Rosiglitazone and pioglitazone  rapidly and

nearly completely absorbed (1-2 hours to peak
concentration)
• Absorption is slightly delayed when taken with
food
• Both agents are extensively metabolised by the
liver
• Rosiglitazone is metabolised mainly to very
weakly active metabolites with lesser activity that
are excreted in urine
 THIAZOLIDINEDIONES

• The metabolites of pioglitazone are more

active  excreted mainly in the bile
• Pioglitazone is metabolised by CYP3A4
• No clinically significant reductions in plasma
concentration of other drugs ( e.g oral
contraceptives)
 THIAZOLIDINEDIONES

• As a monotherapy in non-obese and obese

patients with type 2 diabetes in whom
diabetes is not adequately controlled by
nonpharmacologycal measures
• Can be used in combination with other AD
drugs and in combination with insulin
• Can cause  fluid retention with increased
plasma volume, a reduced haemotocrit, and a
decreased in Hb concentration
 THIAZOLIDINEDIONES

• In Europe, CI CHF

• AHA and ADA : patient treated with a
combination of insulin plus thiazolidinediones 
higher risk of oedema careful clinical
monitoring (check : Hb before starting a
thiazolidinediones)
• Liver function should be assessed by measuring
serum ALT before starting therapy an
subsequently at 2-monthly intervals during the
1st year of treatment
 THIAZOLIDINEDIONES

• Rosiglitazone : 4 mg/d in combination with

sulphonylurea, increasing to 8 mg/d in
combination with metformin
• Pioglitazone : a once-daily dosage of 15 mg/d,
increasing to 30 mg if necessary
• If no effect is observed after 3 months
treatment stop the treatment
• Can be used in the elderly, mild-to-moderate
renal impairment
 ALPHA-
GLUCOSIDASE
INHIBITORS
 ALPHA-GLUCOSIDASE INHIBITORS

• Acarbose and Miglitol

Competitive inhibitors of the intestinal α-

glucosides and reduce post-meal glucose
excursions by delaying the digestion and
absorption of starch and disaccharides
 ALPHA-GLUCOSIDASE INHIBITORS

Acarbose
the first alpha-glucoside inhibitors
 introduce in the early 1990s
Do not cause weight gain
Can reduce postprandial hyperglycemia
Have lowered plasma triglyceride
concentrations in some studies (Lebovitz H.E., et al. 1998)
ALPHA-GLUCOSIDASE INHIBITORS
 ALPHA-GLUCOSIDASE INHIBITORS

Pharmcokinetics:
Is absorbed only < 2%
Is degraded by amilase in the small intestine and
by intestinal bacteria
Some of these degradation products are
systemically absorbed to be eliminated in the
urine
Can be used as monotherapy for pt T2DM that is
inadequately controlled by nonpharmacological
measures
 ALPHA-GLUCOSIDASE INHIBITORS

• Can be a useful first-line treatment in pt who

have a combination of only slightly raised
basal glucose concentrations and more
marked postprandial hyperglycemia
• STOP-NIDDM : confirmed the utility of
acarbose in preventing the transition from
impaired glucose tolerance to diabetes (Chiasson J.L., et
al. 2002)
 ALPHA-GLUCOSIDASE INHIBITORS

• When starting th/ ensure that pt is taking diet

rich in complex CH
• Should be taken with meals
• Starting with a low dose, for example 50 mg/day
• Slowly titrating up over several weeks
• High dosages can occasionally increase liver
enzyme concentrations transaminase
concentration are measured at intervals in pt
receiving the max dosage.
 ALPHA-GLUCOSIDASE INHIBITORS

• If liver enzymes are raised the dosage should

be reduced to a level at which normal enzyme
concentrations are re-etablished
• Aes: gastrointestinal  in th STOP-NIDDM trial:
31% of acarbose –treated pt compared with 19%
on placebo discontinued treatment early
• If dosage is too high undigested oligosaccarides
pass into the large bowel fermented by flora 
flatulance, abdominal discomfort, and sometimes
diarrhoea.  can be minimised by slow titration
 ALPHA-GLUCOSIDASE INHIBITORS

• Hypoglycemia  in combination with a

sulphonylurea or insulin (Krentz A.J., et al. 1994)
 ALPHA-GLUCOSIDASE INHIBITORS
Oral:
-Adults: Dosage must be individualized on the basis of effectiveness and tolerance while not exceeding
the maximum recommended dose

Initial dose: 25 mg 3 times/day with the first bite of each main meal.

Maintenance dose: Should be adjusted at 4- to 8-week intervals based on 1-hour postprandial glucose
levels and tolerance. Dosage may be increased from 25 mg 3 times/day to 50 mg 3 times/day. Some
patients may benefit from increasing the dose to 100 mg 3 times/day.

Maintenance dose ranges: 50-100 mg 3 times/day.

Supplied
Tablet: 25 mg, 50 mg, 100 mg

Maximum dose:
60 kg: 50 mg 3 times/day
>60 kg: 100 mg 3 times/day
INSULIN
 INSULIN
• A small protein with a molecular weight in
humans of 5808
• It contains 51 amino acids arranged in 2 chains
(A nd B) linked by disulfide bridges
• The entire human pancreas contains up to 8
mg of insulin
Model of glucose-induced insulin
release
 The Key Elements in Insulin Secretion

• Glucose transport 2 (GLUT2)

• Glucokinase (GK)
• Mitochondria
• ATP-sensitive K+ channels (K+
• ATPchannels)
• Voltage-dependent Ca2+-channels (VDCC)
• Exocytosis
 INSULIN DEGRADATION

• The liver and kidney 2 main organs that

remove insulin from the circulation
• The liver normally clears blood of
approximately 60% of the insulin released
from pancreas, removing by kidney : 35-40%
• That atio is reversed in insulin-treated diabetis
receiving sc insulin injections
• The half-life of circulating insulin : 3-5 minutes
 Circulating Insulin

• Basal insulin values : 5-15 μU/mL

• Peak rise to 60-90 μU/mL during meals
Diagrammatic structure of stimulation of the insulin receptor
Insulin-activated intracellular signal transduction pathways
INSULIN PREPARATIONS
Principal types and duration of action
of insulin preparations
• 4 principal types of injected insulins are
available:
1. Rapid-acting , with very fast onset and short
duration
2. Short-acting, with rapid onset of action
3. Intermediate-acting
4. Long-acting, with slow onset of action
 Rapid-acting insulin
• Three injected rapid-acting insulin analogs :
Insulin Lispro, Insulin aspart and Insulin
glulisine
• rapid onset and early peak action more
closely mimic normal endogenous prandial
insulin secretion than does regular insulin
• Duration of action : rarely more than 4-5
hours decreases the risk of late postmeal
hypoglicemia
 Rapid-acting insulin
• Have the lowest variability of absorption (app. 5
%) of all available commercial insulins .
• Lispro -> the first monomeric insulin analog to be
marketed, is produced by recombinant
technology : proline at position B28 has been
moved to B29 and lysin at position B29 has been
moved to B28
• Lispro when injected SC quickly dissociates
into monomers and is rapidly absorbed with
onset of action 5-15 minutes and peak activity 1
hour.
 Short-acting insulin
• = regular insulin : a short acting –acting
crystalline zinc insulin made by recombinant
DNA techniques
• Its effect appears within 30 inutes
• Peaks between 2 and 3 hours after SC injection
and generally last 5-8 hours
• Shoul be injected 30-45 or more minutes before
the meal
• Is the only type that should be administrated IV
diabetic ketoacidosis
 Intermediate-acting and long-acting
insulins
NPH (Neutral protamine Hagedon, or isophane)
•  absorption and onset of action are delayed by
combining insulin and protamine
•  onset : 2-5 hours
•  Duration : 4-12 hours
•  it is usually mixed with regular, lispro,aspart,
or glulisine insuline and given 2-4 times daily for
insulin replacement
• Variabiliy of absorption :> 50%
 Intermediate-acting and long-acting
insulins
Insulin glargine :
Has a slow onset : 1-1,5 hours
achieves a max effect after 4-6 hours
Max activity  maintained for 11-24 hours or
longer
once daily
Should not be mixed with other insulins
Has 6-7 fold greater binding than native insulin to
the IGF-1 receptor
 Intermediate-acting and long-acting
insulins
Mixtures of insulin:
Because intermediate-acting NPH insulin require
several hours to reach adequate therapeutic
levels requires supplements of rapid- or short-
acting insulin before meals
Mixed together in the same syringe before
injection
Insulin lispro, aspart and glulisine can be acutely
mixed just before injection with NPH insulin
without affecting their absorption
 Catatan!
• Rapid Insulin (Novorapid), insulin rapid action
untuk mengatasi lonjakan post prandial glucose.
• Long Acting Insulin (Levemir) untuk mengatasi
kebutuhan insulin basal (GDP) efeknya 24 jam
menyerupai insulin endogen dan tidak mempunyai
puncak (peak) sehingga mengatasi nocturnal
Hypoglicemia.
• Mixed Insulin (Novomix) gabungan antara basal
dan prandial insulin digunakan untuk
meningkatkan compliance px sebagai alternatif
insulin basal plus dan basal bolus
 Catatan 2!
• Insulin long acting (Levemir) berfungsi 24
jam dan tidak ada puncak (no peak)
sehingga dapt menghindari hipoglikemia
Nocturnal. Intermediate hanya 12-20 jam
sehingga saat tidur bisa hipoglikemia
 Catatan 3!
• Kapan diberikan IV? Yaitu pada saat krisis
Hiperglikemia
1.KAD (klinis : ketonuri, Kussmaul, Asidosis
metabolic)
2.HONK (pake rumus 3 yes 1 No, hiperglikemi,
keton (-), Kussmaul (-) osmolaritas >325
3.Infark Myocard
4.CVA
5.Sepsis
6.Steroid dosis tinggi
Thank You