by Dr. Rebecca Omozuapo

1. Oral hypoglycemic drugs
Dr. Omozuapo Rebecca
2018

2. Antidiabetic Drugs
 Drugs used to control diabetes mellitus - a chronic
disease that affects carbohydrate metabolism
 2 groups of antidiabetic agents: Insulin & oral
hypoglycemic agents
- Oral hypoglycemic agents = synthetic
preparations that stimulate insulin release or alter
metabolic response to hyperglycemia
- Insulin = a protein secreted from the beta cells
of the pancreas - necessary for carbo metabolism
& an important role in protein & fat metabolism

3. Meglitinide Analogs
Sulphonylureas
Thiazolindinediones
Metformin (Biguanides)
Alpha Glucosidase
Inhibitors

4. •Metformin (Biguanides)
•Glybenclemide, Glicliazide
Glipizide, Glimepiride
• Acarbose , Miglitol, Voglibose
• Repaglinide, Nateglinide
• Rosiglitazone , Pioglitazone
• Sitagliptin, Vildagliptin,
Saxagliptin
Spectrum of Oral Hypoglycaemic
Agents
•Biguanides
•Sulphonylureas
•-Glucosidase
inhibitors
•Meglitinide
analogues
•Thiazolidinediones

5. What is the role of an ideal
oral hypoglycaemic agent?
Conserve islet cell function
- delay the subsequent use of insulin.
Improve patient compliance- single daily
dosing.
Reduce the incidence of hypoglycaemic events

6. Oral hypoglycemic drugs
1. Sulfonylurea drugs
2. Meglitinides
3. Biguanides
4. alpha-glucosidase inhibitors.
5. Thiazolidinediones.
6. Dipeptidyl peptidase-4 (DPP-4) inhibitors

7. Insulin secretagogues
 Sulfonylurea drugs
 Meglitinides
Insulin sensitizers
 Biguanides
 Thiazolidinediones
Others
 Alpha glucosidase inhibitors
 Gastrointestinal hormones
Oral hypoglycemic drugs

8. Insulin secretagogues
Are drugs which increase the amount of insulin secreted
by the pancreas
Include:
• Sulfonylureas
• Meglitinides

9.  First generation are essentially obsolete
 glipizide (Glucotrol), glyburide (Diabeta) and
glimepiride (Amaryl)
 Stimulate insulin release from functioning B cells by
blocking of ATP-sensitive K channels which causes
depolarization and opening of voltage- dependent
calcium channels, which causes an increase in
intracellular calcium in the beta cells, which
stimulates insulin release.
Mechanism of action of sulfonylureas:

10. •displacement from protein binding sites
– salicylates and sulphonamides
•interference with hepatic metabolism
– inducers: rifampicin, phenytoin
– inhibitors: cimetidine
•reduction of renal elimination
– allopurinol, salicylates
Sulfonylureas –
important drug interactions:

11. Mechanisms of Insulin Release

12. Classification of sulfonylureas
Tolbutamide Acetohexamide
Tolazamide
Chlorpropamide Glipizide
glibenclamide
(Glyburide)
Glimepiride
First generation
Long
acting
Short
acting
second generation
Short
acting
Intermediate
acting
Long
acting

13. Pharmacokinetics of sulfonylureas:
 Orally, well absorbed.
 Reach peak concentration after 2-4 hr.
 All are highly bound to plasma proteins.
 Duration of action is variable.
 Second generation has longer duration
than first generation.

14.  Metabolized in liver
 excreted in urine (elderly and renal disease)
Pharmacokinetics of sulfonylureas:

15. Tolbutamide
short-
acting
Acetohexamide
intermediate-
acting
Tolazamide
intermediate
-acting
Chlorpropam
ide
long- acting
Absorption Well Well Slow Well
Metabolism Yes Yes Yes Yes
Metabolites Inactive Active Active Inactive
Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs
Duration of
action
Short
(6 – 8 hrs)
Intermediate
(12 – 20 hrs)
Intermediate
(12 – 18 hrs)
Long
( 20 – 60 hrs)
Excretion Urine Urine Urine Urine
First generation sulfonylureas

16. Tolbutamide:
safe for old diabetic patients or pts with
renal impairment.
First generation sulfonylureas

17. Glipizide - glyburide (Glibenclamide)
 More potent than first generation
 Have longer duration of action.
 Less frequency of administration
 Have fewer adverse effects
 Have fewer drug interactions
Second generation sulfonylureas

18. Glipizide Glibenclamide
(Glyburide)
Glimepiride
Absorption Well Well Well
Metabolism Yes Yes Yes
Metabolites Inactive Inactive Inactive
Half-life 2 – 4 hrs Less than 3 hrs 5 - 9 hrs
Duration of 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs
action short long long
Doses Divided doses
30 min before
meals
Single dose Single dose
Excretion Urine Urine Urine
Second generation sulfonylureas

19. Unwanted Effects:
1. Hyperinsulinemia & Hypoglycemia:
 Less in tolbutamide.
 More in old age, hepatic or renal diseases.
2. Weight gain due to increase in appetite
3. GIT upset.

20. CONTRAINDICATIONS:
 Hepatic impairment or renal insufficiency
 Pregnancy & lactation
 Type I diabetes

21. Repaglinide/Nateglinide
are rapidly acting insulin secretagogues
Meglitinides (non
Sulphonylurea)

22. Mechanism of Action:
Stimulate insulin release from functioning β
cells via blocking ATP-sensitive K-channels
resulting in calcium influx and insulin
exocytosis.

23. Pharmacokinetics of meglitinides
 Orally, well absorbed.
 Very fast onset of action, peak 1 h.
 short duration of action (4 h).
 Metabolized in liver and excreted in bile.
 Taken just before each meal (3 times/day).

24.  Type II diabetes: monotherapy or combined with
metformin (better than monotherapy).
 Specific use in patients allergic to sulfur or
sulfonylureas.
 elderly patients in whom hypoglycaemia is a
concern
Uses of Meglitinides

25. Advantages of
Nateglinide/Repaglinide
 No significant increase in bodyweight
 Can be utillised in mild to moderate renal
failure
 Nateglinide: approved in hepatic failure
Dosage: Repaglinide:
0.5mg/1mg/2mg/4mg per dose per
meal
Nateglinide: 60mg/120mg per dose per
meal
 Lower incidence of hypoglycemia

26. Disadvantages of Metaglinide
derivatives
Works predominantly in mild
hyperglycaemia
Less convincing with fasting
hyperglycaemia

27.  Hypoglycemia.
 Weight gain.
Adverse effects of Meglitinides

28.  Are drugs which increase the
sensitivity of target organs to insulin.
Include
 Biguanides
 Thiazolidinediones (Glitazones)
Insulin sensitizers

29. Metformin
By ADA and EASD guidelines
The primary drug of choice for
diabetes
Insulin sensitizers
Biguanides

30.  Does not require functioning B cells.
 Does not stimulate insulin release.
 Increases peripheral glucose utilization
(tissue glycolysis).
 Inhibits hepatic gluconeogenesis.
 Impairs glucose absorption from GIT.
 Reduces plasma glucagon level.
 LDL &VLDL.
  HDL
Mechanism of action of metformin

31.  orally.
 NOT bound to serum protein.
 NOT metabolized.
 t ½ 3 hours.
 Excreted unchanged in urine
Pharmacokinetics of metformin

32.  Type II diabetes particular, in overweight
and obese people (with insulin resistance).
Advantages:
 No risk of hyperinsulinemia or
hypoglycemia or weight gain (anorexia).
Uses of metformin

33.  GIT disturbances: nausea, vomiting,
diarrhea
 Long term use interferes with vitamin B12
absorption.
 Lactic acidosis: in patients with renal, liver,
pulmonary or cardiac diseases.
 Metallic taste in the mouth.
Adverse effects of metformin

34.  Renal disease.
 Liver disease.
 Alcoholism.
 Conditions predisposing to hypoxia as
cardiopulmonary dysfunction.
Contraindications of metformin

35. Initiate:
- after meals
- 250 to 500mg twice or thrice a day
- Increase gradually if required in 1 or 2 weeks
- mild loose stools in 10% initially, which
reduces gradually
-persistent loose stools in 5%
-Sustained released forms: more effective-
vehicle excreted in stool

36. Metformin:
Dosing from 500mg twice daily to
1 gramme thrice a day
Advantages:
Perpetuates weight loss
Can be combined with insulin
to reduce insulin requirements
Disadvantages:
Nausea, Vomiting and diarhorrea(5%)
Vitamin B12 Deficiency (0.5%)

37. Insulin sensitizers
Thiazolidinediones (glitazones)
 Pioglitazone (Actos)
 Rosiglitazone
 Troglitazone

38. Thiazolidinediones (TZDs)
They increase tissue insulin sensitivity but have
serious ADRs and the EMA recommended in
Sept (2010) that they be suspended from the
EU market:
- Rosiglitazone (Avandia)
has high cardiovascular risks.
- Pioglitazone causes bladder tumors.
- Troglitazone causes hepatitis.

39. Mechanism of action
 Activate PPAR- (peroxisome
proliferator-activated receptor -).
 Decrease insulin resistance.
 Increase sensitivity of target tissues to
insulin.
 Increase glucose uptake and utilization
in muscle and adipose tissue.

40. Pharmacokinetics of pioglitazone
 Orally (once daily dose).
 Highly bound to plasma albumins (99%)
 Slow onset of activity
 Half life 3-4 h
 Metabolized in liver .
 Excreted in urine 64% & bile

41.  Type II diabetes with insulin resistance.
 Used either alone or combined with
sulfonylurea, biguanides.
 No risk of hypoglycemia when used alone.
Uses of pioglitazone

42.  Hepatotoxicity ?? (liver function tests for 1st year of therapy).
 Fluid retention (Edema).
 Precipitate congestive heart failure
 Mild weight gain.
 Potential weight gain (2-4 kg)
 LDL elevation (Mainly over 1st 2 months)
 Oedema
 Worsens Osteoporosis
 Containdicated in Grave’s Ophthalmopathy, Macular
Oedema
 Occasional fluid overload
(therefore avoid in Ischemic heart Disease)
Adverse effects of pioglitazone

43. Contraindications of pioglitazone
 Congestive heart failure.
 Pregnancy.
 Lactating women
 Significant liver disease.

44. -Glucosidase inhibitors
 Acarbose

45.  Are reversible inhibitors of intestinal -glucosidases
in intestinal brush border that are responsible for
carbohydrate digestion.
 decrease carbohydrate digestion and glucose
absorption in small intestine.
 Acarbose (Precose) and miglitol (Glyset)
 Contraindicated in cirrhosis, malabsorption, severe
renal impairment
-Glucosidase inhibitors

46.  Decrease postprandial hyperglycemia.
 Taken just before meals.
 No hypoglycemia if used alone.
-Glucosidase inhibitors

47. Acarbose
 Given orally, poorly absorbed.
 Metabolized by intestinal bacteria.
 Excreted in stool and urine.
Kinetics of -glucosidase inhibitors

48.  Acarbose- 25 mg to 50mg thrice a day
 Miglitol- 25mg to 100mg thrice a day
 Voglibose- 0.2 to 0.3 mg thrice a day

49. Uses
 effective alone in the earliest stages of
impaired glucose tolerance.
 Combined with sulfonylurea in treatment
of Type 2 diabetes to improve blood glucose
control.
Uses of -glucosidase inhibitors

50.  GIT: Flatulence, diarrhea, abdominal
pain
Adverse effects of -glucosidase
inhibitors

51. Contraindications
 an inflammatory bowel disease, such as ulcerative
colitis or Crohn's disease; or any other disease of
the stomach or intestines
 ulcers of the colon
 Intestinal Obstruction

52. Incretin concept
 Insulin secretion dynamics is
dependent on the method of
administration of glucose
 Intravenous glucose gives a marked
first and second phase response
 Oral glucose gives less marked first
and second phase insulin response, but
a prolonged and higher insulin

53. What are the incretins?
 GIP: Glucose-dependent insulinotrophic
polypeptide
Small effect in Type 2 diabetes.
 GLP-1(glucagon-like peptide 1)
augmented in the presence of
hyperglycaemia.
Action less at euglycaemia and in normal
subjects.
 Pituitary Adenylate Cyclase Activating
Peptide (PACAP)

54. GLP-1 localisation
 Cleaved from proglucagon
in intestinal L-cells (and
neurons in
hindbrain/hypothalamus)
 Secreted in response to
meal ingestion
 Cleared via the kidneys

55. GLP-1 Modes of Action in Humans
GLP-1 is secreted
from the L-cells
in the intestine
This in turn…
• Stimulates glucose-dependent
insulin secretion
• Suppresses glucagon secretion
• Slows gastric emptying
Long term effects
demonstrated in animals…
• Increases beta-cell mass and
maintains beta-cell efficiency
• Reduces food intake
Upon ingestion of food…

56. Native GLP-1 is rapidly degraded by DPP-
IV
Human ileum,
GLP-1producing
L-cells
Capillaries,
DiPeptidyl
Peptidase-IV
(DPP-IV)
Adaptedfrom:Hansenetal.Endocrinology1999:140(11):5356-5363

57. Dipeptyl- peptidase inhibitors
Sitagliptin
Vildagliptin
Saxagliptin
Septagliptin
Allogliptin

58. Mechanism of Action of Sitagliptin
Incretin hormones GLP-1 and GIP are released by the intestine
throughout the day, and their levels increase in response to a meal.
Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and
prolonging the actions of these hormones.
Release of
active incretins
GLP-1 and GIP  Blood glucose
in fasting and
postprandial
states
Ingestion
of food
 Glucagon
(GLP-1)
 Hepatic
glucose
production
GI
tract
DPP-4
enzyme
Inactive
GLP-1
X
Sitagliptin
(DPP-4
inhibitor)
 Insulin
(GLP-1 and
GIP)
Glucose-
dependent
Glucose
dependen
t
Pancreas
Inactive
GIP
β cells
α cells
 Glucose
uptake by
peripheral
tissues
30

59. Dipeptidyl peptidase-4 inhibitors
Dipeptidyl peptidase-4 inhibitors (DPP- 4
inhibitors) e.g. Sitagliptin, Vildagliptin

60. (DPP- 4 inhibitors)
Sitagliptin
 Orally
 Given once daily
 half life 8-14 h
 Dose is reduced in pts with renal
impairment

61. Mechanism of action of sitagliptin
Inhibits DPP-4 enzyme, which metabolizes the
naturally occurring incretin hormones
thus increase incretin secretion (gastrointestinal
hormones secreted in response to food). Incretin
hormones decreases blood glucose level by :
 Increasing insulin secretion
 Decreasing glucagon secretion.

62. Mechanism of action of DPP-4
inhibitors

63. Clinical uses
 Type 2 diabetes mellitus as a monotherapy
or in combination with other oral
antidiabetic drugs when diet and exercise
are not enough.
Adverse effects
Nausea, abdominal pain, diarrhea.

64. . Glucagon-like peptide-1 (GLP-1)
agonists (in type 2 DM): increase
pancreatic secretion of insulin:
Exenatide
Bydureon (s.c./7 days):
$323/4 doses, resp.
$4200 per year

65. Liraglutid
Liraglutid
is a GLP-1
agonist,
which reduces,
, HbA1C,
and systolic
blood pressure,
and improves
beta cell function
of the pancreas
(s.c. once a day)

66. Inhibitors of reabsorption
of glucose (SGLT2 inhibitors): p.o.
•Canagliflozin blocks in renal proximal
tubule sodium / glucose co-transporter
protein 2 (SGLT2), which re-absorbed
90% of the filtrated glucose.
The result is increased glucosuria and
plasma glucose levels are lowered.
ADRs: Hypoglycaemia, vulvovaginal candidiasis
urinary tract infections, polyuria, frequent urination.

67. SUMMARY
Class Mechanism Site of
action
Main advantages Main side
effects
Sulfonylureas
Tolbutamide
Glipizide
Glibenclamide
(glyburide)
Stimulating
insulin
production by
inhibiting the
KATP channel
Pancreatic
beta cells
• Effective
• Inexpensive
• Hypoglycemia
• Weight gain
Meglitinides
repaglinide
Stimulates
insulin
secretion
Pancreatic
beta cells
Sulfa free •Hypoglycemia
•Weight gain
Biguanides
Metformin
Decreases
insulin
resistance
Liver
• mild
weight loss
• No hypoglycemia
• GIT symptoms,
• Lactic acidosis
• Metallic taste
Thiazolidinedio
nes
pioglitazone
Decreases
insulin
resistance
Fat, muscle
Hepatoxicity
Edema
ccf
-Glucosidase
inhibitors
Acarbose
Inhibits α-
glucosidase
GI tract Low risk
•GI symptoms,
flatulence
DPP-4 inhibitor
Sitagliptin
Increase
secretin
GI tract

68. Which is the appropriate oral
hypoglycaemic agent to use and
when?

69. Determinants of OAD usage
1)Body Mass Index : Metformin, Gliptins
BMI> 22kg/m2
2)Presence of GI symptoms: Sulpha, Gliptins, Glitazones
3)Renal Dysfunction: Gliptins,Glitazones(+/-),Sulpha (variable)
4) Aging Meglitinides, Gliptins(?)
5) Hepatic Dysfunction Nateglinide, Saxagliptin(?)
6) Compliance Gliptins, Glitazones,
7) Cost Metformin, Sulphas, Glitazones

70. Therapeutic Algorithm
for Oral Hypoglycaemic Drugs…….Today.
Metformin Secretagogue Thiazolidinediones DPPV-4 inhibitor
1. Metformin+
Secretagogue
2. DPPV-4 inhibitor+
Secretagogue
Triple Therapy: A) M +Sec +DPPV
B) M+Thia+DPPV
Metformin
3. DPPV-4 inhibitor
+ Metformin
4.Thiazolidinedione
+ Metformin
Quadruple Therapy!!

71. ADA guidelines, 2008 recommend…

72. Thank You

73. References
 Harrisons principle of internal medicine 19th Ed.
 Kumar & Clarks clinical medicine 7th Ed.
 Davidson's principles and practice of medicine 22nd Ed.
 Emergency Medicine Board Review Series. L Stead, Lippincott
Williams & Wilkins, 2000.
 Emergency Medicine, A comprehensive study guide. Tintinalli, 6th
edition, McGraw Hill, 2004.
 Medscape