ANTI-HYPERGLYCAEMIC DRUGS

PHARMACOLOGY
[DR S. N. KANYIMBA]
INSULIN AND INSULIN ANALOGUES

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Insulin

Insulin biochemistry
• The primary structure of insulin is made from two
polypeptide chains named subunit A and B
• Subunit A consists of 21 amino acids, whereas subunit B
consists of 30 amino acids
• The two chains are connected by two disulfide bridges
• Insulin also forms quaternary structure by creating dimers
using hydrogen bonds and hexamers by bonding with two
zinc ions
• Insulin is stored in the body as a hexamer, while the active
form is the monomer
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Insulin secretion

• Insulin is produced by the pancreatic beta cell

• Insulin secretion is regulated by glucose levels, certain amino acids,
hormones and autonomic mediators
• Secretion is most commonly elicited by elevated plasma glucose levels
• Glucose is taken up into the pancreatic beta cells by the glucose
transporter GLUT-2
• ↑ glucose in beta cells → ↑ glycolytic glucose phosphorylation →
↑ATP → K+ channel blockade → ↓K+ efflux → membrane depolarization
→ opening of Ca2+ channels → ↑ intracellular Ca2+ → exocytotic release
of insulin from storage vesicles
• Continued calcium influx activates insulin gene transcription factors
leading to increased insulin synthesis
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Modulation of insulin synthesis and release

The synthesis and release of insulin is modulated by:

• Glucose (most important), amino acids, fatty acids and ketone
bodies stimulate release
• Glucagon and somatostatin inhibit release

• α2-adrenergic stimulation inhibits release (most important)

• β-adrenergic stimulation promotes release

• Elevated intracellular Ca2+ promotes synthesis and release

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Physiological and pharmacological actions of insulin

Liver: (1) Inhibits glycogenolysis (2) Inhibits gluconeogenesis and increases

glycolysis (3) Inhibits conversion of fatty acids and amino acids to ketoacids
(4) Stimulates glycogen synthesis (5) Increases triglyceride synthesis and very-
low-density lipoprotein formation
Muscle: (1) Increased protein synthesis (2) Increases amino acid transport (3)
Increases ribosomal protein synthesis (4) Increased glycogen synthesis (5)
Increases glucose transport and glycolysis
Adipose tissue: (1) Increases lipogenesis and lipoprotein lipase (2) Increases
glucose transport into cells (3) Decreases intracellular lipolysis
Other effects: Insulin also increases the permeability of many cells to K+
(promotes cellular K+ uptake), magnesium and phosphate ions. The effect on
K+ is clinically important. Insulin activates Na+/K+ ATPases in many cells,
causing a flux of K+ into cells.

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 Mechanism of action of insulin

• Insulin binds to specific insulin receptors (IR) that have tyrosine

kinase activity located in the plasma membrane
• The IR is composed of two alpha subunits and two beta subunits
linked by S-S bonds. The alpha chains are entirely extracellular
and house insulin binding domains, while the linked beta chains
penetrate through the plasma membrane.
• The IR is a tyrosine kinase: it functions as an enzyme that
transfers phosphate groups from ATP to tyrosine residues on
target proteins
• Binding of insulin to the alpha subunits causes the beta subunits
to phosphorylate themselves (autophosphorylation), thus
activating the catalytic activity of the receptor

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 Mechanism of action of insulin …. cont’d

• The activated receptor then phosphorylates a number of

intracellular proteins, which in turn alters their activity, thereby
generating a biological response
• Several intracellular proteins have been identified as
phosphorylation substrates for the insulin receptor and these are
referred to as insulin receptor substrates 1-4 [IRS 1-4])
• When phosphorylated, the IRS are involved in recruitment and
activation of other enzymes that ultimately mediate insulin’s
effects
• Insulin alters the phosphorylation state of key metabolic enzymes,
leading to activation or inactivation of the enzymes
• Insulin induces the transcription of several genes involved in
increasing glucose catabolism and specifically inhibits transcription
of genes involved in gluconeogenesis
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Insulin mediated glucose entry in cells

• Insulin facilitates entry of glucose into muscle, adipose

and several other tissues
• Cells take up glucose is by facilitated diffusion through a
family of glucose transporters (GLUT 1 – 7)
• In many tissues, the major transporter used for uptake of
glucose is GLUT-4. GLUT-4 is made available on the
plasma membrane for glucose uptake through the action
of insulin.

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Sources of insulin
In the past, animal pancreatic tissue (cow and pig) was the source of insulin.
The insulin derived from animal tissue has a slightly different structure from
human insulin. Not used anymore due to problems with purity, allergic
reactions, potency and antibody formation.
Nowadays only HUMAN insulin produced biotechnologically by recombinant
technology is used. It has high purity and low antigenicity.
Insulin analogues
• Include insulin aspart, insulin glulisine, insulin lispro and insulin glargine
• Produced biotechnologically using recombinant technology
• Several amino acids are changed in human insulin to alter its physico-
chemical properties, especially ability to dissociate from hexamer to
monomer.
• Have altered pharmacokinetics profile
• Have same pharmacodynamics as human insulin (equipotent)
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Routes of administration

Insulin is mainly given SC

• Insulin, which is administered in the hexamer form, must be
dissociated to monomers to be absorbable
• Rate of dissociation largely determines absorption and
thereby onset and duration of clinical effect
• Rate of absorption determines onset of actions, drug
concentrations and duration of action
IV administration
• Used only in emergency situations – mostly via infusions
• Suitable only for soluble insulin (regular insulin)
IM is also possible with regular insulin
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Distribution and elimination
Distribution
• Mainly into the extracellular volume
• Insulin receptors are on cell membranes
• Cannot cross membranes by passive diffusion
• Does not cross placenta to affect foetus
Elimination
• More than 90% is eliminated by metabolism (less than 10%
excretion in urine)
• Insulin is degraded in the liver and kidney by glutathione-insulin
transhydrogenase (insulinase) which reduces the disulfide
linkages between the A and B chains, producing two biologically
inactive peptides. Further degradation is by proteolysis.
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Insulin preparations

Rapid acting (ultra-short acting)

• Insulin glulisine, Insulin aspart and Insulin lispro
• Onset: 5-15 min; peak: 60-90 minutes; duration: 3-5 hours. Given SC only.
Short acting
• Regular insulin (soluble, crystalline zinc insulin)
• Onset: 30 – 60 min; peak: 2 – 3 hours; duration: 6 – 8 hours. Given SC, IM and IV.
Intermediate acting
• Isophane insulin (neutral protamine Hagedorn insulin) and Lente insulin
• Onset: 2 - 4 hours; peak: 4 – 10 hours; duration: 12 – 18 hours. Given SC only.
Long acting
• Insulin glargine, Insulin determir and Ultralente
• Onset: 1-4 hrs; duration: 20-24 hrs. Given SC only.
[Lente and Ultralente are no longer manufactured (since 2005)]
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Clinical uses of the insulin preparations

Regular insulin
The insulin preparation used in diabetic emergencies (e.g. diabetic
ketoacidosis) and in the management for rapidly changing insulin
requirements (e.g. post surgery, acute infection)
Rapid acting insulin analogues
Allow for possibility of more flexible treatment regimens and offer increased
convenience (can take just prior to meal). Give better postprandial glycemic
control and are less often associated with hypoglycaemia.
Isophane insulin
Usually mixed with regular insulin for twice daily administration. Can also be
given in combination with lispro, aspart or glulisine insulin.
Long acting insulin preparations
Provide smooth background insulin level (basal insulinization)

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Adverse effects of insulin
• Hypersensitivity reactions: treated with histamine H1 receptor
antagonist and glucocorticoids
• Hypoglycemia: the most frequent and important adverse effect of
insulin
• Lipo-atrophy and lipohypertrophy at injection sites
• Insulin resistance: with chronic insulin resistance (occurs due to
reduced insulin receptor responsiveness), there is need for >200
units/day. Acute insulin resistance is induced by stress (e.g.
infection, trauma, surgery).
Insulin contraindications
• Hypoglycaemia
• Allergy or sensitivity to any ingredient of the product

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Hypoglycaemia

Clinical features
• Sympathetic: nervousness, sweating, tremors, intense hunger,
palpitation
• CNS related: speaking difficulties, weakness
• Advanced CNS function impairment: confusion, drowsiness,
changes in behaviour, seizures and coma
Management of hypoglycaemia
• 10% or 50% dextrose (50% dextrose can cause phlebitis, so it
should be diluted with an equal volume of physiological
saline)
• Glucagon (given IV or IM)
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Drug interactions affecting insulin

Drugs that decrease anti-hyperglycemic effect

Acetazolamide, thiazide and loop diuretics, diazoxide,
progestogen containing hormonal contraceptives, adrenergic
beta2 receptor agonists, phenothiazines, asparaginase,
corticosteroids, protease inhibitors, lithium, phenytoin,
vinblastine, colchicine and thyroid hormones
Drug that increase anti-hyperglycemic effect [potentiate
insulin]
Ethanol, fluoxetine, sulphonamides, β adrenergic blockers,
clonidine, pentamidine, quinidine and quinine

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NON-INSULIN ANTI-HYPERGLYCAEMIC DRUGS

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Classification according to the mechanism of action

Insulin secretagogues Alpha-glucosidase inhibitors

• Sulfonylureas • Acarbose
• Meglitidines • Miglitol

Insulin sensitizers Incretin mimetics and incretin

• Biguanides enhancers

• Thiazolidinediones • Exenatide
• Sitagliptin

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 Biguanides
Class Biguanides
Compound Metformin
Mechanism Activates AMP-kinase
Action(s) • Hepatic glucose production 
• Intestinal glucose absorption 
• Insulin action 
Glucose • Fasting
Lowering Effect • Post Prandial
Advantages • No weight gain
• No hypoglycemia
• Reduction in cardiovascular events and mortality
• Can be combined with insulin to reduce insulin requirements
Disadvantages • Gastrointestinal side effects (nausea, diarrhea, abdominal
cramping)
• Lactic acidosis (rare)
• Vitamin B12 deficiency
• Contraindications: reduced kidney function
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Biguanides

Mechanism of action
The effects of metformin are believed to be due to an increase in the
activity of AMP kinase, a key intracellular regulator of energy
homeostasis
Actions
(1) Decreases the intestinal absorption of carbohydrates (2) Increases
glucose uptake (increases GLUT-4) (3) Increases glucose utilization
(increased glycogen synthase activity) (4) Increases glycolysis via
anaerobic pathway (can result in lactic acidosis) (5) Reduces tissue
insulin resistance: increases glucose uptake and utilization in the
skeletal muscle (6) Inhibits hepatic gluconeogenesis (7) Slows intestinal
absorption of glucose (8) Stimulates glycolysis in enterocytes (9)
Reduces plasma glucagon levels (10) Reduces plasma LDL and VLDL
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Metformin …. cont’d

Pharmacokinetics
• Well absorbed from small intestine
• Excreted unchanged in urine (is not metabolized)
• Half life: 1.5 - 4.5 hours
Clinical use
• Oral anti-diabetic drug of choice in obese type II DM patients
• Has been proven to reduce chronic complications of DM
• Can be used as monotherapy, and in combinations with
insulin, insulin secretagogues and thiazolidinediones

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Metformin: adverse effects & contra-indications

Adverse effects
• GIT disturbances: Include anorexia, nausea, vomiting, abdominal
discomfort, flatulence, diarrhea and metallic taste. They are the most
frequent adverse reactions and occur in up to 20% patients. Are dose
related. Onset rather at the beginning and may be transient.
• Vitamin B12 deficiency (decreased absorption)
• Lactate acidosis: rare but potentially fatal
NB: Does not cause hypoglycemia even in large doses
Contraindications
• Conditions that predispose to lactic acidosis: renal or hepatic
impairment, alcoholism, chronic lung disease, heart failure, sepsis,
metabolic acidosis (predisposing factors to lactic acidosis)
• Others contraindications: malabsorption, GI intolerance, low BMI (<
21kg/m2), marked weight loss, vitamin B12 deficiency

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Sulfonylureas
Class Sulfonylureas
Compound • 1st generation: tolbutamide, chlorpropamide
• 2nd generation: glibenclamide (glyburide), glipizide,
gliclazide (more potent than 1st generation)
• 3rd generation: glimepiride (most potent)
Mechanism Closes KATP channels on β-cell plasma membranes
Action(s)  Insulin secretion
Advantages • Generally well tolerated
• Reduction in cardiovascular events and mortality
Disadvantages • Relatively glucose-independent stimulation of insulin
secretion: Hypoglycemia, including episodes
necessitating hospital admission and causing death
• Weight gain
• Primary and secondary failure

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Sulfonylureas …. cont’d

Mechanism of action
Stimulate insulin release from pancreatic ß cells via binding to the
sulfonylurea (SU) receptor which is the K+ATP channel (ATP sensitive K+
channel). Binding of the drug makes the channel close. This results in reduced
K+ efflux leading to depolarization. Depolarization opens Ca2+ channels, and
increased intracellular calcium drives insulin exocytosis.
Additional effects
They reduce serum glucagon levels and block K+ channels in extra-pancreatic
tissues.
Clinical uses
The sulfonylureas are used as adjuncts to diet and exercise in patient with
type-2 diabetes mellitus. Although they are occasionally used as
monotherapy, sulfonylureas are more commonly used in combination with
other oral anti-diabetic agents in patient who do not reach glycemic goals
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Sulfonylureas: pharmacokinetics

• Well absorbed from gastrointestinal tract

• Food can reduce the absorption of sulfonylureas
• Sulfonylureas are more effective when given 30 minutes
before eating
• Plasma protein binding is high 90 – 99 % (mainly bind to
albumin)
• All sulfonylurea are metabolized by liver and their metabolites
are excreted in urine with about 20 % excreted unchanged
• Sulfonylurea should be administered with caution to patients
with either renal or hepatic insufficiency

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Sulfonylureas: duration of action

Short acting (given three times daily)

• Tolbutamide: rapidly absorbed and absorption not affected by food; rapid
hepatic metabolism
Intermediate acting (given once or twice daily)
• Glibenclamide: rapidly absorbed
• Glipizide: rapidly absorbed, but absorption can be delayed by food
Long acting (given once daily)
• Chlorpropamide and glimepiride
• Chlorpropamide: has active metabolites
• Are rapidly absorbed
• Extensively reabsorbed in the kidney; reabsorption is slowed under basic
pH conditions

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Sulfonylureas: adverse effects

Hypoglycemia
• Most frequent adverse reaction
• Consider dose, patient's age, kidney/liver dysfunction, half-life of
the drug and drug interactions
• Most often seen with chlorpropamide and glibenclamide
• Elderly patients with impaired hepatic or renal functions are
particularly susceptible. Tolbutamide, the short acting SU, is less
likely to cause hypoglycaemia, and is therefore preferred in
patients who are susceptible to hypoglycaemia.
• These cases of hypoglycemia are treated by IV glucose infusion

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 Sulfonylureas …. cont’d

Other adverse effects

• Increased appetite and weight gain: insulin secretion-related effect. Can be a
major problem in obese patients with metabolic syndrome.
• Nausea and vomiting (more common with 1st generation SUs)
• Dermatological reactions (more common with 1st generation SUs)
• Other adverse effects: cholestatic jaundice, hepatic damage, disulfiram-like
effects, anti-diuretic hormone effect (chlorpropamide) and leukopenia
Contraindications
(1) Type 1 diabetes mellitus (2) Pregnancy and lactation (3) Significant hepatic or
renal failure (glibenclamide is contra-indicated in all degrees of renal
impairment)
Precautions
Use caution in patients with renal and hepatic impairment
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Sulfonylureas: drug interactions

Potentiation of hypoglycemic effects

• Displacement of SUs from plasma protein binding sites thereby
increasing their plasma concentrations: salicylic acid, sulfonamides,
indomethacin, penicillin, warfarin
• Inhibition of hepatic microsomal enzymes thereby reducing
metabolism of the SUs: chloramphenicol, warfarin
Attenuation of hypoglycemic effects
• Induction of hepatic microsomal enzymes thereby increasing
metabolism of the SUs: phenytoin, phenobarbital
• Drugs that increase blood glucose: glucagon, thiazides, diazoxide

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Meglitinides

Class Meglitinides
Compound • Repaglinide
• Nateglinide
Mechanism Closes KATP channels on β-cell plasma
membranes
Action(s) Insulin secretion 
Advantages Accentuated effects around meal ingestion
Disadvantages • Hypoglycemia, weight gain
• Dosing frequency

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Meglitinides: nateglinide and repaglinide

• Have the similar mechanism of action as the sulfonylureas: act

by closing ATP-dependent potassium channels in the
membrane of the pancreatic beta cells. This depolarizes the
beta cells, opening the cells' calcium channels, and the
resulting calcium influx induces insulin secretion.
• Have a rapid onset and short duration of action compared to
sulfonylureas
• Nateglinide has a more rapid onset onset of action and is
more specific for pancreatic potassium channels than
repaglinide
• These drugs are metabolized by the liver and should not be
used in patients with hepatic impairment

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Meglitinides …. cont’d
Clinical use
• Used in the management of Type-2 DM
• Often combined with biguanides or thiazolidinediones
• Administered shortly before meals
Meglitinides are useful in the following:
• Elderly patients in whom hypoglycaemia is a concern
• Patients with renal failure
• Patients taking low-dose sulphonylureas who encounter problems with
hypoglycaemia
• Patients with irregular meal patterns
Clinical efficacy
• Improve postprandial glycemia
• Less effective in decreasing fasting blood glucose levels and HbA 1C compared to
sulfonylureas
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Meglitinides …. cont’d

Adverse reactions
• Have a favourable adverse effect profile compared to SUs
• Hypoglycaemia: less frequent, less severe than in SUs
Nateglinide has the lowest hypoglycaemia risk of all
secretagogues. Liver dysfunction makes hypoglycaemia more
likely but renal impairment is not a problem.
• Weight gain: less than with SUs
Drug interactions
Occur with cytochrome P450 enzyme inhibitors/inducers
(meglitinides are metabolized by cytochrome P450 enzymes)

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 Thiazolidinediones (TZD)

Class Thiazolidinediones (Glitazones)

Compound Pioglitazone
Mechanism Activates the nuclear transcription factor PPAR-
(Pioglitazone has some PPAR-α activity as well)
Action(s) Peripheral insulin sensitivity 
Advantages • No hypoglycemia
• HDL cholesterol  (due to PPAR-α activity)
• Triglycerides  (due to PPAR-α activity)
Disadvantages • Weight gain
• Edema
• Heart failure
• Bone fractures

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Thiazolidinediones (TZD)

Class Thiazolidinediones (Glitazones)

Compound Rosiglitazone
Mechanism Activates the nuclear transcription factor PPAR-
Action(s) Peripheral insulin sensitivity 
Advantages No hypoglycemia
Disadvantages • LDL cholesterol 
• Weight gain
• Edema
• Heart failure
• Bone fractures
• Increased cardiovascular events (mixed
evidence)

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 TZDs: Mechanism of action

Activate nuclear peroxisome proliferator activated receptor

gamma (PPAR-γ)

Increased insulin receptors in

adipocytes & hepatocytes
Increased fatty acid
translocase

GLUT-1 and GLUT-4 proteins

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TZD: pharmacodynamics

TZDs act by increasing tissue sensitivity to insulin

Mechanism of action
• TZDs are agonists on peroxisome proliferator-activated receptor γ (PPAR-γ)
nuclear receptors which are located in adipocytes, myocytes and hepatocytes
• PPAR-γ receptors modulate expression of genes involved in lipid and glucose
metabolism, insulin signal transduction and adipocyte metabolism
Effects
TZDs predominantly affect liver, skeletal muscle and adipose tissue:
• Liver: reduce gluconeogenesis
• Muscle: increase glucose uptake
• Adipose tissue: increase glucose uptake and decrease fatty acid synthesis
TZDs reduce plasma glucose and triglycerides

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TZDs …. cont’d

Pharmacokinetics
• Well absorbed and highly bound to plasma proteins (>99%)
• Metabolized to active metabolites with long half-life
Adverse effects
(1) Weight gain (2) Fluid retention (3) May worsen or precipitate
heart failure (4) Headache, fatigue, GIT disturbances (5) LDL
elevation with rosiglitazone (6) Worsen osteoporosis
Contraindications
(1) Grave’s ophthalmopathy (2) Macular oedema (3) Heart failure

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TZDs: clinical effects and use

Actions of TZDs require the presence of insulin

Enhance effectiveness of both endogenous and exogenous
insulin
• Glucose lowering effect is slow in onset: maximum achieved
in 1-2 months
• Euglycemics rather than hypoglycaemics
• Effective in 70% of new NIDDM patients
• Dyslipidemia correction in the metabolic syndrome
• Reduction of diabetic incidence in patients with pre-diabetes
• Can be used as monotherapy and in combination with other
drugs
• Can be combined effectively with insulin
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TZDs …… cont’d

Precautions
• Therapy should not be initiated if the patient exhibits clinical
evidence of acute or chronic liver disease, or increased serum
transaminase levels
• Due to risks of myocardial infarction restrict use of
rosiglitazone to those currently using it or those whose blood
sugar is not controlled with any other meds and prefer not to
use other drugs

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Alpha-glucosidase inhibitors

Class α-Glucosidase inhibitors

Compound • Acarbose
• Miglitol
Mechanism Inhibits intestinal α-glucosidase
Action(s) Intestinal carbohydrate digestion and
absorption slowed
Advantages • Nonsystemic medication
• Postprandial glucose 
Disadvantages • Gastrointestinal side effects (gas,
flatulence, diarrhea)
• Dosing frequency

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Alpha-glucosidase inhibitors: acarbose and miglitol

Mechanism of action
• Reducing intestinal absorption of starch, oligosaccharides
and disaccharides by inhibiting the action of intestinal brush
border alpha-glucosidases
• Disaccharides and oligosaccharides must be cleaved
enzymatically in the gut to be absorbable. Apha-
glucosidases are the enzymes responsible for this action.
• Alpha-glucosidase inhibitors decrease digestion of starch
and disaccharides and thus decrease post-prandial glucose
levels

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Alpha-glucosidase inhibitors …. cont’d

Advantages: reduce postprandial hyperglycaemia and do not

cause hypoglycaemia
Clinical use: Can be used as monotherapy in type-2 DM and with
all classes including insulin. Taken just before ingestion of first
portion of the meal.
Adverse effects: GIT disturbances – flatulence, diarrhea,
abdominal pain
Contra-indications: (1) Inflammatory bowel disease (ulcerative
colitis or Crohn's disease) (2) Intestinal obstruction (3) Kidney
disease

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Incretins
• Incretins are a group of gastrointestinal hormones that stimulate a
decrease in blood glucose levels
• Incretins do so by causing an increase in the amount of insulin released
from the beta cells of the islets of Langerhans after eating, before blood
glucose levels become elevated
• They also inhibit glucagon release from the alpha cells of the Islets of
Langerhans
• The two major incretin hormones are glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic polypeptide [GIP] (also known as:
gastric inhibitory peptide)
• Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl
peptidase-4 (DPP-IV)
• Type 2 diabetics exhibit little incretin effect (levels of GLP-1 and the
insulinotropic response to GIP are decreased)

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Incretin mimetics
Class GLP-1 receptor agonists (incretin mimetics)
Compound • Exenatide
• Liraglutide
Mechanism Activates GLP-1 receptors (β-cells/endocrine pancreas;
brain/autonomous nervous system
Action(s) • Insulin secretion  (glucose-dependent)
• Glucagon secretion  (glucose-dependent)
• Slows gastric emptying
• Satiety  (reduces appetite)
Advantages • Weight reduction
• Potential for improved β-cell mass/function
Disadvantages • Gastrointestinal side effects (nausea, vomiting, diarrhea)
• Cases of acute pancreatitis observed
• C-cell hyperplasia/medullary thyroid tumors in animals
(liraglutide)
• Injectable
• Long-term safety unknown

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 Exenatide
• Exenatide is a 39-amino acid synthetic analogue of GLP-1
• GLP-1 receptor agonist
• Actions: stimulates post-prandial insulin secretion, decreases glucagon
secretion, slows gastric empting, reduces appetite and promotes pancreatic
beta cell proliferation
• Administered SC twice daily (given within 60 minutes prior to a meal)
• Major adverse effects: nausea, vomiting, diarrhea. Increases the risk of
acute pancreatitis
• Not recommended as monotherapy: used as add on therapy with SU,
metformin or TZD
• Increases the risk of hypoglycemia when added to SU treatment
• Major advantage is weight loss (~5 kg) as well as maintained effect
(preserves beta cell function)
• Avoid in severe renal impairment
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Incretin enhancers

Class DPP-4 inhibitors (incretin enhancers)

Compound • Sitagliptin
• Vildagliptin
• Saxagliptin
• Linagliptin

Mechanism Inhibits DPP-4 activity, prolongs survival of

endogenously released incretin hormones
Action(s) • Active GLP-1 concentration 
• Insulin secretion 
• Glucagon secretion 
Advantages • No hypoglycemia
• Weight “neutrality”
Disadvantages • Occasional reports of urticaria/angioedema
• Cases of pancreatitis observed
• Long-term safety unknown (cancer ?)
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Dipeptidylpeptidase IV (DPP-IV) inhibitors

Mechanism of action: Reversible, competitive inhibitors of DPP-IV.

Inhibit the breakdown of GLP-1 by DPP-4 therefore increasing GLP-1
levels resulting in increased glucose-dependent insulin release and
decreased level of circulating glucagon and hepatic glucose production
Actions: (1) Enhance insulin secretion in response to an oral glucose
load (2) Suppress post-prandial glucagon secretion (3) Preserve beta
cell function
Clinical use: Effective as monotherapy and can be used in conjunction
with sulfonylureas, metformin or a thiazolidinedione. Given orally.
Adverse effects: Nasopharyngitis, headache, hypoglycaemia [when
given with sulfonyureas], nausea, vomiting, diarrhoea, rarely
pancreatitis

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Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

• Glucose is freely filtered by the renal glomeruli and is

reabsorbed in the proximal tubules by the action of sodium-
glucose transporters (SGLTs). Sodium-glucose transporter 2
(SGLT2) accounts for 90% of glucose reabsorption, and its
inhibition causes glycosuria and lowers glucose levels in
patients with type 2 diabetes.
• The SGLT2 inhibitors canagliflozin, dapagliflozin, and
empagliflozin are approved for clinical use. They are given
orally either as monotherapy, or in combination with insulin
or other drugs.

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Amylin analogs

Class Anti-hyperglycemic synthetic analog

Compound • Pramlintide
Mechanism • Amylinomimetic
Action(s) • Glucagon secretion  (glucose-dependent)
• Slows gastric emptying
• Satiety 
Advantages • Potential weight loss
Disadvantages • Meal time injections
• Nausea
• Hypoglycemia in combination with insulin

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Pramlintide

• Pramlintide is a synthetic amylin analog. Amylin is a

polypeptide stored and secreted by beta-cells of the pancreas,
and it acts with insulin to reduce blood sugar
• Pramlintide acts to slow gastric emptying, decrease glucagon
secretion and decreases appetite
• Administered SC, typically with insulin
• Adverse effects: hypoglycaemia, nausea

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ENDE

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