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.

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