1) Oral hypoglycemic agents work by enhancing insulin secretion, increasing insulin sensitivity, or reducing glucose absorption. The main classes include sulfonylureas, meglitinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, amylin analogues, SGLT-2 inhibitors, and dopamine D2 receptor agonists. 2) Sulfonylureas work by blocking ATP-sensitive potassium channels, stimulating insulin secretion. Common side effects include hypoglycemia and weight gain. 3) Biguanides like metformin increase insulin sensitivity by decreasing hepatic glucose output and intestinal glucose absorption

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