Newer Anti-Diabetic Drugs

NEWER ANTI-DIABETIC DRUGS


NEWER ANTI-DIABETIC DRUGS

Introduction:

Classification of anti-diabetic drugs:

New generation anti-diabetic drugs

1. Incretins:

Introduction:

  • Glucose invokes insulin release more effective, when given orally than, i.v.
  • ‘INCRETIN’ are chemical signals from gut, released in response to
  • Incretin – Acts on pancreatic β-cell → Anticipatory insulin release.

Ex:

  • glucagon-like peptide-1 (GLP1)
  • glucose-dependent insulinotropic polypeptide (GIP)
  • vasoactive intestinal peptide (VIP)
  • pancreozymin-cholecystokinin.

MOA:

  • Enhances insulin release by increasing cAMP formation in β cells.
  • In DM type-2 – GLP-1 secretion is reduced.

Action of GLP-1 –

  • Main action in DM:
    • Little stimulatory effect on insulin secretion (at normoglycemic concentration)
    • Note: Sulfonylureas & other insulin secretagogues don’t have this effect.
    • Hence, GLP-1 has lower risk of causing hypoglycemia.
  • Other actions:
    • Suppress glucagon secretion.
    • Preserves islet cell integrity & decreases its apoptosis.
    • Delays gastric emptying causing reduced appetite

Properties of GLP-1:

  • Endogenous GLP-1 rapidly broken – By dipeptidyl peptidase-4 (DPP-4)
  • Half-life – 1-2 mins only.

Drugs related to incretins:

  • Two ways pharmacologically, incretins can be employed – 
  • Via GLP-1 receptor agonists
  • Via DPP-4 inhibition – Oral active inhibitors of DPP-4 enzyme – Indirectly acting insulin secretagogues.

2. GLP-1 receptor agonists:

  • Acts by mechanism similar to GLP-1.
  • Administered subcutaneously.
  • Ex:
    • Exenatide & Liraglutide.
    • Latest drugs – Albiglutide & Dulaglutide.

Advantages – Promote weight loss.

Adverse effect –

  • Nausea (Common)
  • Acute pancreatitis

Contra-indication – Family history of medullary thyroid cancer or MEN-2.

Individual drugs –

Liraglutide –

  • Longer-acting (once daily).
  • Does not require dose adjustment in renal failure.
  • Also used for obesity management.

Exenatide –

  • Twice daily
  • Dose adjustment needed (should be reduced).

3. DPP-4 Inhibitors:

MOA:

  • Prolongs endogenous GLP-1 action, by inhibiting GLP-1 metabolism through DPP-4.
  • Orally effective.
  • Eg: Sitagliptin, vildagliptin, saxagliptin, alogliptin, empagliflozin & Linagliptin.

Advantages – Unlike incretin-mimetic drugs, do not cause nausea or weight loss.

Disadvantages:

  • Require dose adjustment in renal failure except linagliptin.
  • Vildagliptin – Cause hepatitis.

Adverse effect – Nasophargyingitis & URT infections.

4. Sodium glucose co-transporter-2 inhibitors (SGLT-2 inhibitors):

Note on SGLT-2:

  • Sodium  glucose co-transporter-2 [SGLT-2] present in proximal tubules.
  • Glucose is freely filtered across glomerulus & is 100% reabsorbed in proximal tubules, via SGLT-2.

MOA:

  • SGLT-2 inhibitors acts by inhibiting this transporter –> Causing glucosuria in diabetics –> causes weight loss.
  • Effective orally.
  • Efficacy reduced in renal failure.
  • Eg: Dapagliflozin & canagliflozin.

Adverse effect – Increased incidence of UTI & genital infections.

Dapagliflozin:

  • Higher rates of breast & bladder cancers.
  • After single daily dose → Produce round-the-clock glucosuria & lowers blood glucose levels.
  • Glycosuria predisposes to,
    • Urinary & genital infections
    • Electrolyte imbalance
    • Increased urinary frequency.

5. Dopamine D2 agonist:

  • Bromocriptine mesylate:
    • An adjunct to diet & exercise.
    • Improves glycemic control in type -2 diabetes.
    • MOA: Dopamine alters insulin resistance – By acting on hypothalamus.
    • Bromocriptine targets D2 receptors.

6. Amylin analogs/ Amylin:

Introduction:

  • Amylin/ ‘Islet amyloid polypeptide’ (IAP).
  • Produced by pancreatic β cells.
  • Reduces glucagon secretion from α cells.
  • Delays gastric emptying.
  • Retards glucose absorption
  • Acts on brain – Promotes satiety.

Drugs included – Pramlintide:

  • Synthetic analog of islet amyloid polypeptide (IAPP).
  • Administered by subcutaneous route.

Uses – Only drug apart from insulin, approved for both type 2 & type 1 DM treatment.

MOA:

  • Decreases glucagon secretion
  • Delays gastric emptying
  • Decreases appetite
  • Can cause hypoglycemia & weight loss.

Exam Important

NEWER ANTI-DIABETIC DRUGS

1. Incretins:

  • Incretin – Acts on pancreatic β-cell –> Anticipatory insulin release.

Ex:

  • glucagon-like peptide-1 (GLP1)
  • glucose-dependent insulinotropic polypeptide (GIP)
  • vasoactive intestinal peptide (VIP)
  • pancreozymin-cholecystokinin.

MOA:

  • Enhances insulin release by increasing cAMP formation in β cells.
  • In DM type-2 – GLP-1 secretion is reduced.

Action of GLP-1 –

  • Little stimulatory effect on insulin secretion (at normoglycemic concentration) – Hence, GLP-1 has lower risk of causing hypoglycemia.
  • Other actions:
    • Suppress glucagon secretion.
    • Preserves islet cell integrity & decreases its apoptosis.
    • Delays gastric emptying causing reduced appetite

Properties of GLP-1:

  • Endogenous GLP-1 rapidly broken – By dipeptidyl peptidase-4 (DPP-4).
  • pharmacologically, incretins can be employed – 
  • Via GLP-1 receptor agonists
  • Via DPP-4 inhibition – Oral active inhibitors of DPP-4 enzyme – Indirectly acting insulin secretagogues.

2. GLP-1 receptor agonists:

  • Acts by mechanism similar to GLP-1.
  • Administered subcutaneously.
  • Ex:
    • Exenatide & Liraglutide.
    • Latest drugs – Albiglutide & Dulaglutide.

Advantages – Promote weight loss.

Adverse effect – Nausea (Common)

Contra-indication – Family history of medullary thyroid cancer or MEN-2.

Individual drugs –

Liraglutide –

  • Longer acting (once daily)
  • Does not require dose adjustment in renal failure
  • Also used for obesity management.

Exenatide –

  • Twice daily
  • Dose adjustment needed (should be reduced).

3. DPP-4 Inhibitors:

MOA:

  • Prolongs endogenous GLP-1 action, by inhibiting GLP-1 metabolism through DPP-4.
  • Orally effective.
  • Eg: Sitagliptin, vildagliptin, saxagliptin, alogliptin, empagliflozin & Linagliptin.

Advantages – Do not cause nausea or weight loss.

Disadvantages:

  • Require dose adjustment in renal failure except linagliptin.
  • Vildagliptin – Cause hepatitis.

4. Sodium-glucose co-transporter-2 inhibitors (SGLT-2 inhibitors):

MOA:

  • SGLT-2 inhibitors act by inhibiting this transporter –> Causing glucosuria in diabetics –> causes weight loss.
  • Effective orally.
  • Efficacy reduced in renal failure.
  • Eg: Dapagliflozin & canagliflozin.

Adverse effect – Increased incidence of UTI & genital infections.

Dapagliflozin:

  • Higher rates of breast & bladder cancers.
  • After single daily dose → Produce round-the-clock glucosuria & lowers blood glucose levels.
  • Glycosuria predisposes to,
    • Urinary & genital infections
    • Electrolyte imbalance
    • Increased urinary frequency.

5. Dopamine D2 agonist:

  • Bromocriptine mesylate:
    • An adjunct to diet & exercise.
    • Improves glycemic control in type -2 diabetes.
    • MOA: Dopamine alters insulin resistance – By acting on hypothalamus.
    • Bromocriptine targets D2 receptors.

6. Amylin analogs/ Amylin:

Drugs included – Pramlintide:

  • Synthetic analog of islet amyloid polypeptide (IAPP).
  • Administered by subcutaneous route.
  • Approved for both type 2 & type 1 DM treatment.

MOA:

  • Decreases glucagon secretion
  • Delays gastric emptying
  • Decreases appetite
  • Can cause hypoglycemia & weight loss.

 

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