ANTIDIABETIC AGENTS

Classification of antidiabetics agents

Cont.
6) Incretins
Gastric inhibitory polypeptide (GIP)
Glucagon-like peptide-1 (GLP-1)
7) Dipeptidyl Peptidase-IV (DPP-IV) Antagonists
Sitagliptin and Vildagliptin
8) SGLT2 Inhibitors (Na-glucose cotransporters)
Canagliflozin (only approved drug),
dapagliflozin, ipragliflozin

ROLE OF ANTIDIABETIC AGENTS

FIRST GENERATION SULPHONYLUREA COMPOUNDS

* Good for patients with renal impairment

** Patients with renal impairment can expect long t1/2

SECOND GENERATION SULPHONYLUREA COMPOUNDS

PHARMACOLOGICAL EFFECTS

OF SULPHONYLUREAS

1. Hypoglycemic effect
2. Antidiuretic effect
chlorpropamide & glibenclamide
3. Anti-platelet aggregation effect
gliclazide

Hypoglycemic mechanism
1. Rapid mechanism: stimulation of insulin secretion

2. Long term profit involved mechanism

Inhibition of glucagon secretion by pancreas cells;
Ameliorating insulin resistance
Increase insulin receptor number & the affinity to insulin

CLINICAL USE
1. Type 2 diabetes mellitus (T2DM)
2. Diabetes insipidus: chlorpropamide
SIDE EFFECTS OF SULPHONYLUREAS
1) Nausea, vomiting, abdominal pain, diarrhea
2) Hypoglycemia
3) Dilutional hyponatraemia & water intoxication
(Chlorpropamide)
4) Disulfiram-like reaction with alcohol
(Chlorpropamide)
5) Weight gain
6) Blood dyscrasias
(not common; less than 1% of patients)
- Agranulocytosis
- Haemolytic anaemia
- Thrombocytopenia

CONTRAINDICATIONS OF SULPHONYLUREA
1) Type 1 DM ( insulin dependent)
2) Parenchymal disease of the liver or kidney
3) Pregnancy, lactation
4) Major stress

DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF

SULPHONYLUREAS
WARFARIN
SULFONAMIDES
SALICYLATES
PHENYLBUTAZONE
PROPRANOLOL
ALCOHOL
CHLORAMPHENICOL
FLUCONAZOLE

MEGLITINIDES

MECHANISM OF ACTION
Bind to the same KATP Channel as do sulfonylureas to
cause insulin release from -cells
They act like the sulfonylureas, but they do not have
the sulfonylurea moiety hence a weaker binding
affinity and faster dissociation from the SUR1 binding
site.
This increases the concentration of intracellular
potassium, which causes the electric potential over
the membrane to become more positive.
Thisdepolarizationopens voltage-gatedCa
2+channels. The rise in intracellular calcium leads to
increased fusion ofinsulingranulae with the cell
membrane, and therefore increased secretion of
(pro)insulin

 Include mitiglinide, repaglinide

and nateglinide
Short duration of action and a low
risk of hypoglycaemia.

CLINICAL USE
Approved as monotherapy and in combination with
metformin in type 2 diabetes
Taken before each meal, 3 times / day
Does not offer any advantage over sulfonylureas
Given to patients allergic to sulfur or sulfonylurea

SIDE EFFECTS
Hypoglycemia
Wt gain ( less than SUs )
Caution in pts with renal & hepatic impairment.

BIGUANIDES
Metformin is the only drug of this class presently available in market
It does not cause hypoglycaemia
MECHANISM OF ACTION
1. Increases peripheral glucose utilization
2. Inhibits gluconeogenesis
3. Impairs absorption of glucose from the gut
ADVANTAGES OF METFORMIN OVER SULPHONYL
UREAS
Does not cause hypoglycemia
Does not result in weight gain
( Ideal for obese patients )

MOA of metformin

SIDE EFFECTS

1. Metallic taste in the mouth

2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea, abdominal
discomfort)
3. Vitamin B 12 deficiency (prolonged use)
4. Lactic acidosis ( rare, exclusive in renal & hepatic failure)

PHARMACOKINETICS
Taken orally
Rapidly absorbed ( Peak approx. 1hr )
Metabolized by liver
t1/2 = 1 hr
Duration of action 4-5 hr

CONTRAINDICATIONS

1. Hepatic impairment
2. Renal impairment
3. Alcoholism
4. Heart failure
INDICATIONS
1. Obese patients with type 11 diabetes
2. Alone or in combination with sulfonylureas

-GLUCOSIDASE INHIBITORS
Alpha-glucosidase inhibitorsare oralanti-diabetic drugsused
forT2DMthat work by preventing the digestion of carbohydrates
(such asstarchandsucrose). Carbohydrates are normally
converted into simple sugars (monosaccharides), which can be
absorbed through the intestine. Hence, alpha-glucosidase
inhibitors reduce the impact of carbohydrates onblood sugar.

Examples of alpha-glucosidase inhibitors include:

Acarbose (Precose)
Miglitol (Glyset)
Voglibose

Acarbose is anoligosaccharide, whereas miglitol resembles a

monosaccharide. Miglitol is fairly well absorbed by the body, as
opposed to acarbose. Moreover, acarbose inhibits pancreatic
alpha-amylase in addition to alpha-glucosidase.

Mechanism of action
Alpha-glucosidase inhibitors are saccharides that act as
competitive inhibitors of enzymes needed to digest carbohydrates
specifically alpha-glucosidase enzymes in the brush border of the small
intestines.
The membrane-bound intestinal - glucosidases hydrolyze
oligosaccharides, trisaccharides, and disaccharides to glucose and other
monosaccharides in the small intestine.
Acarbose also blocks pancreatic alpha-amylase in addition to inhibiting
membrane-bound alpha-glucosidases. Pancreatic alpha-amylase
hydrolyzes complex starches to oligosaccharides in the lumen of the
small intestine.
Inhibition of these enzyme systems reduces the rate of digestion of
carbohydrates. Less glucose is absorbed because the carbohydrates are
not broken down into glucose molecules.
In diabetic patients, the short-term effect of these drugs therapies is to
decrease current blood glucose levels: the long-term effect is a small
reduction in hemoglobin A1c level

Since alpha-glucosidase inhibitors are competitive

inhibitors of the digestive enzymes, they must be taken at
the start of main meals to have maximal effect. Their
effects on blood sugar levels following meals will depend
on the amount ofPHARMACOKINETICS
complex carbohydrates in the meal.
Given orally
Not absorbed from intestine except small amount
t1/2 3 - 7 hr
Excreted with stool

SIDE EFFECTS

Flatulence
Loose stool or diarrhea
Abdominal pain
Alone does not cause hypoglycemia

THIAZOLIDINEDIONES (GLITAZONES)

Also known as TZDs. Examples:

Rosiglitazone, Pioglitazone, Lobeglitazone

MECHANISM OF ACTION
Lowerinsulin resistancein muscle and fat.
Also reduce glucose produced by theliver.
Increase target tissue sensitivity to insulin by:
reducing hepatic glucose output & increase glucose uptake &
oxidation in muscles & adipose tissues.
They do not cause hypoglycemia (similar to metformin and
acarbose )

 Thiazolidinediones or TZDs act by activatingPPARs

(peroxisome proliferator-activated receptors), a group
ofnuclear receptors, with greatest specificity forPPAR
(gamma).
The endogenousligandsfor these receptors are free
fatty acids(FFAs) andeicosanoids.
When activated, the receptor binds toDNAin complex
with theretinoid X receptor(RXR), another nuclear
receptor, increasingtranscriptionof a number of specific
genesand decreasing transcription of others.
The main effect of expression and repression of specific
genes is an increase in the storage of fatty acids in
adipocytes, thereby decreasing the amount of fatty acids
present in circulation. As a result, cells become more
dependent on the oxidation ofcarbohydrates, more
specificallyglucose, in order to yield energy for other
cellular processes.

PPAR transactivation
Insulin resistance is decreased
Adipocyte differentiation is modified
VEGF-induced angiogenesis is inhibited
Leptin levels decrease (leading to an
increased appetite)
Levels of certain interleukins (e.g. IL-6)
fall
Antiproliferative action
Adiponectin levels rise

 TZDs also increase the synthesis of certain

proteins involved in fat and glucose metabolism,
which reduces levels of certain types of lipids, and
circulating free fatty acids.
TZDs generally decrease triglycerides and
increase high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol (LDL-C).
PPAR transrepression
Binding of PPAR to coactivators appears to
reduce the levels of coactivators available for
binding to pro-inflammatory transcription factors
such asNF-B; this causes a decrease in
transcription of a number of pro inflammatory
genes, including various interleukins and tumour
necrosis factors.

PHARMACOKINETICS
-

99% absorbed
Metabolized by liver
99% of drug binds to plasma proteins
Half-life 3 4 h
Eliminated via the urine 64% and feces 23%

ADVERSE EFFECTS
-

Mild to moderate edema

Wt gain
Headache
Myalgia
Hepatotoxicity
Rosiglitazone, a certain glitazone, was suspended
from allowed use by medical authorities in
Europe, as it has been linked to an increased risk
of heart attack and stroke

 Experimental, failed and non-marketed

agents include:
Ciglitazone
Darglitazone
Englitazone
Netoglitazone
Rivoglitazone
Troglitazone(Rezulin), which was
withdrawn from the market due to an
increased incidence of drug-induced
hepatitis.

WHAT ARE INCRETINS?

Hormones produced by the gastrointestinal tract in response to incoming
nutrients, and have important actions that contribute to glucose homeostasis
Two hormones:
- Gastric inhibitory polypeptide (GIP)
.
- Glucagon-like peptide-1 (GLP-1).

Gastric Inhibitory Polypeptide (GIP)

Secreted by the K cells of the proximal gut. However, type 2 diabetes
patients are resistant to its action (high blood level), making it a less
attractive therapeutic target.

Glucagon-like peptide-1 (GLP-1)

A 30-amino acid peptide secreted in response to the oral ingestion of
nutrients by L cells, primarily in the ileum and colon.
There are GLP-1 receptors in islet cells and in the central nervous system,
among other places.
GLP-1 is metabolized by the enzyme dipeptidyl peptidase-IV (DPP-IV)

ACTIONS OF GLP-1
It enhances glucose-dependent insulin secretion.
Inhibits glucagon secretion and therefore hepatic glucose
production.
Slows gastric emptying.
Increases satiety resulting in less food intake.
Appears to stimulate insulin gene transcription and insulin
synthesis.
In animal studies it increases beta-cell mass by:
- Decreasing beta cell apoptosis.
- Stimulating the growth of new beta cells
IMPORTANT: As glucose levels approach the normal range, the GLP-1
effects on insulin stimulation and glucagon inhibition declined (glucose
dependence - reduction of hypoglycemia. - therapeutic advantage

EXENATIDE (GLP-1 agonist)

The first incretin-related therapy available for patients with type 2 diabetes.
Naturally occurring peptide from the saliva of the Gila Monster (A
poisonous American lizard).
Has an approximate 50% amino acid homology with GLP-1.
Binds to GLP-1 receptors and behaves as GLP-1.

Recent Advances in incretin mimetics

Liraglutide: Another GLP-1 analog with longer half-life,
similar to exenatide with once-daily injection
Long acting exenatide: Highly effective with once weekly
injection

LIXISENATIDE 2013
ALBIGLUTIDE -2014
DULAGLUTIDE-2014
SEMAGLUTIDE- (ORAL)

DIPEPTIDYL PEPTIDASE-IV (DPP IV) ANTAGONISTS

GLIPTINS

Class oforal hypoglycemicsthat blockDPP-4 (DPP-IV)

used to treatT2DM.
Glucagonincreasesblood glucoselevels, and DPP-4
inhibitors reduce glucagon and blood glucose levels.
The mechanism of DPP-4 inhibitors is to increase
incretinlevels (GLP-1andGIP),which inhibitglucagon
release, which in turn increases insulinsecretion,
decreases gastric emptying, and decreases
blood glucoselevels.
The concept is to allow the endogenous GLP-1 to remain in
circulation for a longer period.
DPP-IV inhibitors are oral, rather than injectable
Associated with a low incidence of hypoglycemia or gastrointestinal
side effects

Drugs belonging to this class are :

Sitagliptin (FDA approved 2006, marketed by Merck & Co. as
Januvia)
Vildagliptin (EU approved 2007, marketed in the EU by Novartis as
Galvus)
Saxagliptin (FDA approved in 2009, marketed as Onglyza)
Linagliptin (FDA approved in 2011, marketed by Eli and
Boehringer Ingelheim)
Gemigliptin (approved in Korea in 2012, marketed by LG Life
Sciences)
Anagliptin (approved in Japan in 2012)
Teneligliptin (approved in Japan in 2012)
Alogliptin (FDA approved 2013, marketed by Takeda
Pharmaceutical Company)
Trelagliptin (approved for use in Japan in 2015)
Dutogliptin (being developed by Phenomix Corporation), Phase III
Omarigliptin (MK-3102) (approved in Japan in 2015, developed by
Merck & Co.; research showed that omarigliptin can be used as
once-weekly treatment and generally well-tolerated throughout
the base and extension studies)

Sitagliptin and Vildagliptin

Sitagliptin and vildagliptin are the first agents in this class to have received
FDA approval.
They are indicated as monotherapy and in combination with metformin,
thiazolidinediones and insulin

Adverse effects
Nasopharyngitis,headache,nausea,
heart failure, hypersensitivity and skin
reactions. They may cause severe
joint pain.
In those taking sulphonylureasthere is
an increased risk oflow blood sugar.
Cancer : Precancerous changes in the
pancreas of rats and organ donors treated
with sitagliptin
Increased risk ofheart failurewith
saxagliptin and alogliptin, prompting the
FDA in 2016 to add warnings to the
relevant drug labels

AMYLIN ANALOGS

Amylin,orislet amyloid
polypeptide(IAPP), is a 37-residue
peptide hormone.It is cosecreted with
insulinfrom the pancreatic-cellsin the
ratio of approximately 100:1. Amylin
plays a role in glycemic regulation by
slowing gastric emptying and promoting
satiety, thereby preventing
post-prandialspikes in blood glucose
levels.
Amylin agonists display some of the
beneficial effects of GLP-1.

 Pramlintide, a synthetic amylin analog can be

used as a potential adjunctive therapy in
patients with type 1 and type 2 diabetes.
Pramlintide has been shown primarily to
reduce prandial glucose excursions, which
have been suggested to play a role in the
development of cardiovascular complications
Amylin agonists given at bedtime to type 2
diabetic patients could induce -cell rest,
analogous to somatostatin and potassium
channel openers
Pramlintide is currently under evaluation for
approval as an adjunctive therapy for insulintreated diabetic patients.