Oral hypoglycaemic agents dr jayesh vaghela

1. ORAL
HYPOGLYCAEMIC
AGENTS
DR. JAYESH VAGHELA

2. A. Enhance Insulin
Secretion:
1) Sulfonylurias
(KATP channel
blockers)
2) Meglitinide /
Phenylalanine
analogues
3) GLP-1 receptor
agonists
4) DPP-4 inhibitors
B. Overcome Insulin
Resistance:
1) Biguanides (AMPK
Activator)
2) Thiazolidinediones
C. Miscellaneous:
1) Alpha-
Glucosidase
inhibitors
2) Amylin
analogue
3) D2 receptor
agonist
4) SGLT-2
inhibitor
CLASSIFICATION

3. SULFONYLUREAS
(SU)

4. K+ ↑ K+
K+
Depolarization
Ca++
↑ Ca++
Stored
Insulin
MECHANISM OF ACTION
SU / Megli
SUR1

5. EXTRAPANCREATIC ACTION
• After few months of therapy,
• Down regulation of sulfonylurea receptors (SUR1) on beta cells
⇓
Decreased insulinaemic action of SU
⇓
But, improvement in glucose tolerance is maintained
⇓
Increased insulin receptors
⇓
It sensitizes the target tissue to action of insulin (esp. in liver)

6. Do not cause hypoglycaemia in - Pancreatectomized animals, and
- Type 1 DM
⇓
Confirms its indirect action through pancreas
 Drawback:
• Increase insulin secretion at any glucose (even at low) concentration
⇓
Risk of severe & unpredictable hypoglycaemia

7. • Well absorbed Orally
• Highly plasma protein bound – 90-98%
• Low volume of distribution (0.2-0.4 L/kg)
• Onset of action is approximately 1-3 hrs
• Duration of action of second generation is around 24 hrs
• Metabolized by the liver, and the metabolites are excreted in the urine.
• Second-generation agents are approximately 100 times more potent than first
generation.
PHARMACOKINETICS

8.  Drug that enhances sulfonylureas action :
A) Displace from Protein binding:
• Phenylbutazone, Sulfinpyrazone, Salicylates, Sulfonamides
B) Inhibit metabolism/excretion:
• Cimetidine, warfarin, chloramphenicol
C) Synergise with or prolong PD action:
• Propranolol, lithium, theophylline, Salicylates
DRUG INTERACTIONS

9.  Drug that decrease sulfonylureas action:
A) Induce metabolism:
• Phenobarbitone, Phenytoin, Rifampicin
B) Opposite action/suppress insulin release:
• Corticosteroids, thiazides, OC pills, furosemide

10.  Hypoglycemia:
• Most common in elderly patients
• With impaired renal and hepatic function
• With long acting agents
 Increase Weight: 1 – 3 kg
 Hypersensitivity: Photosensitivity, rash, purpura
 Disulfiram-like reaction if taken with alcohol
 Secreted in milk: - not given to nursing mothers
ADVERSE DRUG REACTIONS

11. MEGLITINIDE
OR
D-PHENYLALANINE
ANALOGUES
Quick & Short-lasting
Insulinaemic action

12.  Mechanism of action:
• Similar to SU
 Indication:
• Fast onset & short-lasting insulin release
• Before each major meal to control postprandial hyperglycaemia
• Dose is omitted if meal is missed
• Only in selected Type 2 DM patients who suffer P.P. hyperglycaemia, or
• To supplement Metformin / Long acting insulins
REPAGLINIDE

13.  Action:
• Mainly stimulates 1st phase of insulin secretion
⇓
• Faster onset & shorter lasting action than repaglinide
 Indication:
• 10 min before meal
NATEAGLINIDE

14.  ADRs:
• Headache, Dyspepsia, Arthralgia, Weight gain
• Dizziness, flu-like symptoms
• Dose:
 Repaglinide: - 0.25 - 4 mg
 Nateglinide: - 60 - 120 mg

15. GLP-1
RECEPTOR
AGONISTS
INJECTABLE
AGENTS

16. GLP – 1
(GLUCAGON – LIKE PEPTIDE – 1)
Glucose ingestion
⇓
GLP-1 released from gut
⇓
Induces insulin release
Inhibits glucagon release
Slows gastric emptying
Suppresses appetite
Promotes beta cell health
⇓
Degraded by DPP-4 (Dipeptidyl peptidase-4)
Present in capillary endothelial cells, kidney, liver, immune cells
⇓
Not suitable for clinical use

17. EXENATIDE
• Mechanism of action:

18. • Synthetic analogue of GLP – 1 receptor
• DPP – 4 resistant
 Benefits:
 Lowers fasting & postprandial blood glucose
 Lowers HbA1c
 Lowers body weight
 Dose: 5 – 10 mcg subcutaneous injection once daily
 ADRs:
• Nausea, vomiting

19. • Tightly bound to plasma proteins
• T1/2: > 12 hours
• Duration of action > 24 hours
 ADRs:
• Nausea, diarrhoea
• Safely given in renal failure patients
LIRAGLUTIDE

20. DPP – 4
INHIBITORS

21. INTRODUCTION
• DPP-4 is a serine protease that is widely distributed throughout the body
• DPP-4 inhibitors provide nearly complete and long lasting inhibition of DPP-4
• Increase the proportion of active GLP-1 from 10-20% to nearly 100%
• Sitagliptin and alogliptin: - Competitive inhibitors of DPP-4
• Vildagliptin and saxagliptin - Covalent binding

22. Selective inhibition of DPP-4 enzyme which inactivates GLP-1
⇓
Increased GLP-1 levels
Prolonged actions
⇓
1) Increase insulin secretion
2) decrease glucagon release
3) delay gastric emptying
4) decreases the appetite by acting at the level of hypothalamus.
MECHANISM OF ACTION

23. • Absorbed effectively from small intestine
• Circulate primarily in unbound form
• Excreted mostly unchanged in urine
• Saxagliptin is metabolized by CYP 3A4 , so should be used cautiously with CYP
inhibitor and enhancer
 Doses:
• Sitagliptin: 100 mg OD before meals.
• Vildagliptin:50 mg OD before meals.
• Saxagliptin:5 mg OD before meals.
PHARMACOKINETICS

24. SITAGLIPTIN
• Actions:
• Increases postprandial insulin release
• Decrease glucagon secretion
• Lowers meal-time & fasting blood glucose in Type 2 DM
• HbA1c lowering: Sitagliptin = Metformin
• Used as monotherapy when metformin can not be used

25.  ADRs:
• Nasopharyngitis ∵ Prevention of Substance P degradation
• Cough
 Dose reduction:
• Needed in renal impairment
• Not in liver disease

26. VILDAGLIPTIN
The complex dissociates very slowly
⇓
Persistent DPP-4 inhibition even after drug is
cleared from circulation
⇓
Longer duration of action (12 – 24 hours)
Despite short t1/2 (2 – 4 hours)

27. o Saxagliptin:
• Recently marketed in India
o Alogliptin:
• Marketed in Japan
o Linagliptin:
• Recently approved for use in USA

28. BIGUANIDES
( AMPK
ACTIVATORS )

29. DIFFERENCES FROM SULFONYLUREAS
• Little / No hypoglycaemia in non-DM
• Even in DM patients, rare hypoglycaemia
• Does not stimulate pancreatic beta cells
• Improves lipid profile in Type 2 DM

30. MECHANISM OF ACTION

31. • Major action: Inhibition of hepatic gluconeogenesis, which decrease glucose
output
• Increases uptake and disposal of glucose by skeletal muscle, which reduces
insulin resistance
• Promotes peripheral glucose utilization through anaerobic glycolysis
• By interfering with mitochondrial respiratory chain
• Retards intestinal absorption of glucose, other hexoses, vitamin B12
ACTIONS

32. o ADRs:
• GIT: - anorexia, Nausea, abdominal pain, bloating, metallic taste
• Lactic acidosis
• Vit B12 deficiency
o Contraindications:
• Hypotension
• Heart failure
• Severe respiratory, hepatic, renal diseases
• Alcoholics (risk of acidosis)

33. o Advantages:
• Non-hypoglycaemic
• Weight loss promoting
• Prevents macro & microvascular complications
• No acceleration of beta cell exhaustion/failure in Type 2 DM
• Efficacy is equivalent to other OHAs
o Uses:
• 1st choice drug for all Type 2 DM patients (except when contraindicated)
• Infertility: improve ovulation in PCOD
• Mitigation of insulin resistance
• Lowering insulin levels

34. THIAZOLI
-DINEDIONE

35.  Fatty tissue is the major site of action
Acts as agonist to a nuclear receptor called Peroxisome Proliferator
Activated Receptor-gamma (PPAR-γ)
• PPAR-γ is expressed mainly in adipose tissue, skeletal muscle and liver
• Activation of PPAR- γ
⇓
Promotes transcription of insulin responsive genes which control glucose
and lipid metabolism
MECHANISM OF ACTION

36. 2) Increase the number of GLUT-4 glucose transporter in cell membrane
of skeletal muscles and adipose tissue
⇓
promotes peripheral uptake and utilization of glucose
3) Inhibits gluconeogenesis
⇓
decrease hepatic glucose output

37. PIOGLITAZONE
• Also acts on PPARα to induce expression of reverse cholesterol transporter &
some apoproteins
⇓
↓ TG, ↑ HDL
o ADRs:
• Plasma volume expansion
• Edema
• Weight gain
o C/I:
• Liver disease & CHF

38. o Use:
• Type 2 DM to supplement SUs / Metformin, & insulin resistance
• Not effective if beta cell failure has set in
• Stopped if HbA1c reduction is < 0.5 % at 6 months
• Not to be used in pregnancy

39. ALPHA-
GLUCOSIDASE
INHIBITORS

40. • Inhibits α - glucosidase enzyme
(which facilitates digestion of complex starches, oligosaccharides and
disaccharides into monosaccharides which is important for absorption)
⇓
Reduces postprandial digestion and absorption of carbohydrates
Lowers the post meal hyperglycemia.
• Pk: mainly excreted through kidney .
MECHANISM OF ACTION

41.  Adverse Effect :
• Flatulence, Diarrhea
• Abdominal pain (fermentation of undigested carbohydrates in lower GIT)
• Cutaneous hypersensitivity
 C/I:
Bowel obstruction, Inflammatory Bowel disease
Renal failure
 Doses:
Acarbose : 50-100 mg
Miglitol : 50-100 mg Voglibose: 0.4-0.6 mg

42. AMYLIN
ANALOGUE

43. AMYLIN
• Synonym: “IAP – Islet Amyloid Polypeptide”

44. PRAMLINTIDE
• Synthetic amylin analogue
• S.c. injection before meal
⇓
Decrease postprandial hyperglycaemia
Centrally mediated anorectic action
 Benefit:
• Decreased body weight

45. SGLT – 2
INHIBITOR

46. • Kidney continuously filters glucose through glomerulus
• Most of it reabsorbed back from the proximal tubule by a transporter called
SGLT- 2 (Sodium-Glucose cotransport – 2)
• Inhibiting SGLT- 2
⇓
Decreases the amount of glucose reabsorption from PT,
Increases its excretion

47. MECHANISM OF ACTION

48. DAPAGLIFLOZIN
• Single daily dose - Round the clock glucosuria
- Decreased blood glucose levels
o Disadvantages :
• Because of polyuria there would be more polydipsia
• Increased risk of urinary bacterial/fungal infection
• Risk of Na+2 loss
• Electrolyte imbalance
• Urinary frequency

49. o Advantages:
• No hypoglycemia as they are excreting only the excess of glucose from
the blood and not inducing insulin secretion
• Weight loss
• Improve insulin resistance by depleting toxic level of glucose
• Beneficial for HT with DM because of their diuretic effect.

50. DOPAMINE
D – 2
AGONIST

51. BROMOCRIPTINE
• US-FDA approved it in 2009 as adjunctive
treatment to Type 2 DM
• Taken early in the morning
⇓
Act on the hypothalamic dopaminergic control of
circadian rhythm of hormones release (GH, PRL,
ACTH, etc.)
⇓
Reset it to reduce insulin resistance
• Dose: - started at 0.8 mg OD orally up to 4.8 mg OD

52. NEWER ANTIDIABETIC
DRUGS

53. • Bile acid metabolism is abnormal in Type 2 DM
• There are reports that bile acid binding resins lowers plasma glucose in
DM 2 patients
• Bile acid sequestrants could reduce intestinal glucose absorption
• They may act as a signaling molecules through nuclear receptors, which
act as a glucose sensor.
BILE ACID BINDING RESINS

54. • Only bile acid sequestrate specifically approved for the treatment of T2DM
o Adverse Effect :
• Constipation
• Abdominal pain
• Dyspepsia
• Nausea
• Triglyceridemia
COLESEVELAM

55. • Glucokinase enzyme plays a key role in glucose homeostasis
• Glucokinase activators can lower glucose levels in type 2 diabetes
• Piragliatin is a glucokinase activator
• Has an acute glucose lowering action
PIRAGLIATIN

56. • Found in the skin of red grapes and in other fruits
• Activator of Silent mating-type Information Regulation 2
homolog 1 (SIRT1)
• Useful in the therapy of DM 2 because
1) It possesses the ability to scavenge oxidatively generated free radicals
2) enhanced activity of multiple proteins, including peroxisome-proliferator
activated receptor gamma (PPAR gamma)
RESVERATROL

57. EPALRESTAT
• Glucose → Aldose reductase → Sorbitol → Excess in DM → Deposited in
nerves → Diabetic neuropathy
• Epalrestat → Aldose reductase inhibitor →delays sorbitol deposition in
sciatic nerve / other tissues → Delays diabetic neuropathy
• Trials → Improvement in nerve conduction, Neuropathic pain
• ADRs: Nausea, Vomiting, Elevated liver enzymes
• Dose: 50 mg TDS before meals

58. CHOICE OF INITIAL GLUCOSE LOWERING
AGENT

59. • The level of hyperglycemia should influence the initial choice of therapy
• Drugs approved for monotherapy:
• Insulin secretagogues - Biguanides
• Thiazolidinediones - alpha-glucosidase inhibitors
• Each class has its unique advantages.
Hyperglycaemia FPG (mg / dl) Treatment
Mild to moderate < 250 Single agent
Moderate 250 – 300 Add 2nd agent
Severe > 300 Insulin

60. OHA Are Most Effective In Patients With
• Age > 40 years at onset of disease
• Obesity at time of presentation
• Duration of disease < 5 years when starting therapy
• FBS < 200 mg/dl
• Insulin requirement < 40 U/day
• No complication e.g. ketosis, others.

61. • Insulin secretagogues, biguanides,DPP-4 inhibitor and TZd improve glycemic
control to a similar degree (1-2% reduction in A1c) and are more effective than
alfa-glucosidase inhibitor.
• Insulin secretagogues and α -glucosidase inhibitors begin to lower the plasma
glucose immediately,
• whereas the glucose-lowering effects of the biguanides and thiazolidinediones are
delayed by several weeks to months
• Biguanides, α-glucosidase inhibitors, DPP-IV inhibitors, and Tzd do not directly
cause hypoglycemia
• Most individuals will eventually require treatment with more than one class of oral
glucose-lowering agents or insulin, reflecting the progressive nature of type 2 DM

62. Algorithm for DM treatment

63. Algorithm for
DM treatment

64. • Combination therapy with drugs that affect different molecular targets, and that
have different mechanisms of actions
 Advantage:
• Improves glycemic control while using a lower dose of each drug
• Reduces adverse reaction
 Example:
• Combination of - An insulin sensitizer (e.g., a TZD or metformin)
- Insulin or an insulin secretagogue (e.g., a sulfonylurea)
1. improve glycemic control in a poorly controlled Type II diabetic patient and
2. lower the dose of each drug required to achieve a therapeutic effect
COMBINATION THERAPY

65.  Tzds and metformin:
• Both are insulin sensitizers but with different mechanisms of action
• Can also be used together effectively
• Combining two different insulin secretagogues does not improve
therapeutic outcomes
• The exact combination of therapies can be guided by an estimation of the
beta cell secretory reserve in the patient.

66. • Alvin C. Powers and David D’Alessio. Endocrine pancreas and pharmacotherapy of
diabetes mellitus and hypoglycaemia.In : Bruton LL, editor. Goodman & Gilman’s –The
Pharmacological basis of therapeutics. 12th edition. NewYork : Mc Graw Hill Publication;
2011. p. 1237- 54.
• Olanow CW, Schapira AH. Diabetes Mellitus. In: LongoDL, editor :Harrisons’s principles of
internal medicine. 18th edition. New york:Mc Grew hill;2012. P.3317-35.
• Tripathi KD. Essentials of Medical Pharmacology. 6th ed. New Delhi : Jaypee brothers
medical publishers; 2009. p. 270-80.
• Sharma HL & Sharma KK. Principles of Pharmacology. 2nd ed. New Delhi: Paras
publication; 2012. p. 636-41.
References