oral antidiabetic agents
Oral Therapy for Type 2 Diabetes Target Sites of
Action
 Glucose
 Insulin
 Glucose
uptake
Adipose
tissue
absorption
Pancreas
secretion
Gut
Sulfonylureas
Repaglinide
Acarbose
Miglitol
 FFA output
Rosiglitazone
Pioglitazone
 Hyperglycemia
Liver
Muscle
 Hepatic glucose
output
Avandia® (rosiglitazone maleate) PI. GlaxoSmithKline, February
2001.
Actos® (pioglitazone HCl) PI. Takeda Pharmaceuticals, May 2001.
Prandin® (repaglinide) PI. Novo Nordisk, August 2000.
Precose® (acarbose) PI. Bayer Corporation, October 1999.
GlysetTM (miglitol tablets) PI. Pharmacia/Upjohn, September 1999.
Glucophage® (metformin HCl) PI. Bristol-Myers Squibb, June 2001.
Metformin
Rosiglitazone
Pioglitazone
Glucose
uptake

Rosiglitazone
Pioglitazone
Metformin
1. Sulfonylurea
• In the presence of viable pancreatic β-cells,
sulfonylureas enhance the release of endogenous
insulin, thereby reducing blood glucose levels
• Binding of a sulfonylurea to its receptor (SUR1)
inhibits the efflux of potassium ions through the
channel and results in depolarization
Sulfonylurea- Mechanism of action
ADP
ATP
Sulfonylurea-binding site
ADP
ADP
Voltage-dependent
Ca++ channel closed
ADP
ADP
K
+
ATP-binding
site
Ca
ATP-sensitive K+ channel
From Ashcroft FM, Gribble FM. Diabetologia. 1999;42:903-909.
Berne R, Levy M. Physiology. Chapter 46;851-875.
K
+
Kir 6.2
++
Sulfonylurea- Mechanism of action
Sulfonylurea
ATP
ADP
ATP
ATP
ATP
Ca++
K
+
Ca++
Exocytosis of insulincontaining granules
ATP-sensitive K+
channel closed
K 6.2
IR
From Ashcroft FM, Gribble FM. Diabetologia. 1999;42:903-919.
Bryan J, Aguilar-Bryan L. Biochemica et Biophysica Acta. 1999;1461;285-303.
Berne R, Levy M. Physiology. Chapter 46;851-875.
depolarization
1. Sulfonylurea- First generation sulfonylurea
1) First generation sulfonylurea
• Agents: Acetohexamide, chlorpropamide, tolazamide,
& tolbutamide
• Are not frequently used in the management of DM
2) Second generation sulfonylurea
• Agents: glyburide, glipizide, & glimepiride
• Prescribed more than are the first-generation agents
because they have fewer adverse effects and drug
interactions
1. Sulfonylurea- Second generation sulfonylurea
• Agents: glyburide, glipizide, & glimepiride
• The second-generation sulfonylureas are prescribed more
than are the first-generation agents because they have
fewer adverse effects and drug interactions
• The second-generation agents are approximately 100 times
more potent than are those in the first generation. Although
their half-lives are short (3 to 5 hours), their hypoglycemic
effects are evident for 12 to 24 hours, and they often can be
administered once daily
1. Sulfonylureas- Adverse reactions
1) Hypoglycaemia: which can be severe and prolonged.
The highest incidence occurring with chlorpropamide
and glyburide and the lowest with tolbutamide
2) Weight gain: stimulate appetite (probably via their
effects on insulin secretion and blood glucose)
3) Other less frequent SEs: nausea and vomiting,
cholestatic jaundice, agranulocytosis, aplastic and
hemolytic anemias, generalized hypersensitivity
reactions, and dermatological reactions
4) Hyponatremia: chlorpropamide
Sulfonylureas
Dicumarol
Chloramphenicol
Monoamine oxidase inhibitors
Phenylbutazone
Reduce hepatic
metabolism of
sulfonylureas
Phenylbutazone
Salicylate
Sulfonamide
Displace sulfonylureas
from plasma proteins
Increased hypoglycemic action
of sulfonylurea drugs
Allopurinol
Probebecid
Phenylbutazone
Salicylate
Sulfonamide
Decrease urinary
excretion of
sulfonylureas or their
metabolites
2. Rapeglinide andNateglinide
• Like sulfonylureas, repaglinide stimulates insulin release
by closing ATP-dependent potassium channels in
pancreatic β cells
• Much less potent and shorter duration of action than most
sulfonylureas: less hypoglycemia and weight gain
• Have rapid onset and offset kinetics: indicated for use in
controlling postprandial glucose excursions. It is taken
before each meal
• Insulin sensitizers
• Insulin sensitizers lower blood glucose by improving
target-cell response to insulin without increasing
pancreatic insulin secretion
• Their effects do not depend upon functional islet cells
and generally do not cause hypoglycemia
• Two classes of oral agents improve insulin action:
I. Biguanides
II. Thiazolidinediones
1. Biguanides
• Metoformin (Glucophage®) is the only currently
available biguanide
• It does not cause insulin release from the pancreas and
generally does not cause hypoglycemia, even in large
doses
• Metformin reduces glucose levels, largely by inhibiting
hepatic gluconeogenesis (↓hepatic glucose production).
• Metformin is recommended as first-line therapy in the
majority of type 2 patients who are obese and who fail
treatment with diet alone: decreases the risk of
macrovascular as well as microvascular disease
•
1. BiguanidesMechanism of action
• Possible minor mechanisms of action include:
1. Impairment of renal gluconeogenesis **
2. Slowing of glucose absorption from the GIT
3. Increased glucose to lactate conversion by
enterocytes (intestinal absorptive cell)
4. Direct stimulation of glycolysis* in tissues
5. Increased glucose removal from blood
6. Reduction of plasma glucagon levels
1. Biguanide- Adverse reactions
• GIT (anorexia, nausea, vomiting, abdominal
discomfort, and diarrhea): dose-related, tend to occur
at the onset of therapy, and are often transient. Can be
minimized by increasing the dosage of the drug slowly
and taking it with meals
• Intestinal absorption of vitamin B12 and folate often is
decreased during chronic metformin therapy
1. Biguanide- Contraindications: risk of lactic acidosis
• Causes: reduced drug elimination or reduced tissue
oxygenation
• Patients with renal insufficiency, alcoholism,
hepatic disease, or conditions predisposing to
tissue anoxia (eg, chronic cardiopulmonary
dysfunction)
• Radiocontrast administration can cause acute
kidney failure in patients with diabetes .
Metformin therapy should be halted on the day
of radiocontrast use and restarted a day or two
later after confirmation that renal function has
not deteriorated
Thiazolidinediones
• Agents: pioglitazone and rosiglitazone
• They all act to decrease insulin resistance and
enhance insulin action in target tissues
• Tzds are selective agonists for nuclear peroxisome
proliferator-activated receptor-γ (PPARγ)
• Tzds promote glucose uptake and utilization and
modulates synthesis of lipid hormones or
cytokines and other proteins involved in energy
regulation in adipose tissue
Thiazolidinediones- Adverse reactions
• Rosiglitazone increase the risk of angina pectoris or
myocardial infarction: proposed mechanisms include
an increase in weight, an expansion of plasma volume
following a reduction in renal sodium excretion, or a
direct effect to increase vascular permeability
• Liver function should be monitored in patients
receiving Tzds
• Increased fracture risk in women, which is postulated
to be due to decreased osteoblast formation
• Pioglitazone is associated with an increased risk of
bladder cancer
α-Glucosidase Inhibitors
• Acarbose and miglitol are competitive inhibitors of the αglucosidases (sucrase, maltase, glucoamylase, and
dextranase) in the intestinal brush border
• They slow the absorption of carbohydrates; the postprandial
rise in plasma glucose is blunted in both normal and
diabetic subjects
• They do not cause hypoglycemia
• The drugs should be administered at the start of a meal
• SEs: Dose-related flatulence, diarrhea, and abdominal pain
• Contraindications: inflammatory bowel disease, colonic
ulceration, or intestinal obstruction
Amylin analogs: Pramlintide
• MOA: reduces glucagon secretion, slows gastric emptying,
and centrally decreases appetite
• It is administered SC in addition to insulin (type 1 and 2) in
those who are unable to achieve their target postprandial
blood sugars
• Concurrent rapid- or short-acting mealtime insulin doses
should be decreased by 50% or more
• ADEs: hypoglycemia and GIT symptoms (nausea,
vomiting, and anorexia)
• Contraindication: diabetic gastroparesis (delayed stomach
emptying) or a history of hypoglycemic unawareness
Incretin-based therapies
“gut derived hormones that stimulate
insulin secretion with nutrient ingestion”
In ● cre ● tin
Intestine Secretion Insulin
More recently, investigators have reported that impairments in the secretion levels and/or
the activity of key incretin hormones may also play a significant role in the development
and progression of hyperglycemia in type 2 diabetes
Incretin-based therapies
• The incretin effect is believed to be mediated by
mainly two intestinal derived peptides: glucose
dependent insulinotropic polypeptide (GIP) and GLP-1
(glucagon-like peptide-1)
• Circulating GLP-1 is rapidly (1 to 2 minutes)
inactivated by the dipeptidyl peptidase IV enzyme
(DPP-IV). Thus, GLP-1 must be infused continuously
to have therapeutic benefits (limited benefit)
Physiology of GLP-1 secretion and action on
various tissues
Hypothalamus
-
Liver
Food & water intake
Muscle
+ Glycogenesis
+ Glycogenesis
GLP-1
Adipose
tissue
+ Lipogenesis
Stomach
-
Pancreas
+ Insulin secretion
+ Somatostatin secretion
E.J. Verspohl Pharmacology & Therapeutics 124 (2009) 113–138
Acid secretion & gastric
emptying
Glucagon secretion
GLP-1 increases insulin secretion & inhibits the secretion of
glucagon in a glucose-dependent way
Food ingestion
Glucose dependent
 Insulin
(GLP-1 and GIP)
Release of active
incretins GLP-1
and GIP
Pancreas
Glucose
uptake by
peripheral tissue
Beta cells
Alpha cells
GI tract
DPP-4
enzyme
Blood
glucose
Glucose dependent
 Glucagon
(GLP-1)
Inactive
GLP-1
Inactive
GIP
Glucose
production
by liver
Incretin-based therapies
• Two different approaches can be used:
1. GLP-1 receptor agonists: that directly stimulate
GLP-1 receptors on the pancreas and gut to give
effects similar to those of endogenous GLP-1 (e.g.
exenatide, liraglutide)
2. Enhance endogenous incretins by inhibiting their
degradation
(DPP-4
inhibitors):
thereby
extending the activity of endogenously produced
GLP-1 and GIP
GLP1 receptor agonist: Exenatide, Liraglutide,
Albiglutide, Dulaglutide
• Approved as a SC injectable in type 2 DM
• Major adverse effects are nausea (about 44% of users)
and vomiting and diarrhea. The nausea decreases with
ongoing exenatide usage
• Weight loss is reported in some users, presumably
because of the nausea and anorectic effects
• A serious and, in some cases, fatal adverse effect of
exenatide is necrotizing and hemorrhagic pancreatitis
Dipeptidyl peptidase-4 (DPP-4)inhibitors:
Sitagliptin, saxagliptin, & others
• Major action is to increase circulating levels of GLP-1 and
GIP.
• Approved as a monotherapy in the U.S. and as an add-on
therapy to metformin
• Common adverse effects include nasopharyngitis, upper
respiratory infections, and headaches
• Rarely, severe allergic reactions have been reported
Sodium-glucose co-transporter 2
(SGLT2) inhibitors
• Agents: Canagliflozin , Dapagliflozin , Empagliflozin
• MOA: inhibit glucose reuptake by SGLT2 in the proximal
tubule of the kidney
• This action is independent of insulin secretion and activity
and, therefore, these agents are not considered to
predispose to hypoglycaemia
• SEs: increased incidence of genital infections and UTIs,
and euglycemic ketoacidosis
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