Metformin - Drug Of Choice For Type 2 Diabetes

Metformin :

Metformin belongs to the class of biguanibes. Other agents belonging to this class 

are phenformin & buformin (which were withdrawn due to lactic acidosis)

Mechanism of action -

• Exerts range of action countering insulin resistance via post receptor signalling pathway for insulin & lower blood glucose
• Glucose lowering efficacy of metformin requires at least some insulin
• There is a glucose lowering effect due to reduction of hepatic gluconeogenesis
• Metformin enhances glucose uptake in skeletal muscle by Increasing insulin sensitive glucose  transporters (GLUT 4)
• Increases glycogen synthesis
• Reduces triglyceride
• Decreases fasting and post prandial insulin
• Decreases body weight
• Increased fibrinolytic activity 
• Decreased platelet aggregability
• Provides protection against vascular complications (MI / stroke)

Pharmacokinetics -

• Rapidly but incompletely absorbed
• Little plasma protein binding
• Excreted unchanged in urine within 12 hours by tubular secretion 
• No interference  with co-administered drugs
• T1/2 is 6 hours
• Oral bio availability 50-60 %
• Peak concentration at 2 hours
• Cimetidine is the only drug known to compete for clearence with metformin and cause  significantly increase in plasma metformin concentration

Indication and contra-indication -

Indication :

• First line drug for obese type II diabetes
• Suggested to be used in patients with gestational diabetes and pregnancy associated glucose intolerance or type II diabetes following failure of dietary therapy
• Can be  used along with other oral hypoglycemic agents and insulin
• Polycystic ovarian disease – ovulation can resume in women with an ovulatory PCOS

ContraIndication:

• Careful administration should be done if estimated GFR is less than 45 ml/minute/ 1.73 m sq or creatinine clearance less than 60 ml per minute or serum creatinine > 130 micro mol/ litre
• Cardiac or respiratory insufficiency
• Hypoxia
• Hypo tension
• Septicaemia
• Liver disease
• Alcohol abuse
• History of metabolic acidosis
• It has been suggested that It should  be stopped temporarily for surgery under general anaesthesia & if IV contrast has to be given.

Dosage -

Maximum effective Dose 2 gm 

(although in some countries 2.5 – 3 gm 

is being used)

It is available as IR (immediate 

release), XR (extended release), SR 

(Sustained release) formulations

Efficacy -

Decreases fasting blood sugar 

by 2-4 mmol/ l

Decreases HbA1C by 1-2 %

Side Effects -

• 
  

  Abdomen discomfort
• Diarrhea 
• Lactic acidosis
• Vitamin B12 Malabsorption
• 
  

  Macrocytosis

Brand Names -

• Glycomet 
• Glyciphage
• Gluformin
• Glucophage XR
• Carbo phage SR
• Riomet
• Obimet
• Cetapin XR

α-Glucosidase Inhibitors - Acarbose,miglitol,Voglibose

α-Glucosidase Inhibitors - Acarbose,miglitol,Voglibose

Mode Of Action :

• Competitive inhibition of α-glucosidase enzyme in brush border of enterocytes lining the intestinal villi
• Binds with high affinity to enzyme
• Prevents enzymes from cleaving disaccharides & oligosaccharides into monosaccharides
• Delays completion of carbohydrate absorption
• Delays glucose absorption
• Also Alters release of GIP & GLP1 which enhance insulin secretion
• Probably reduce post-prandial insulin concentrations through  attenueted rise in post-prandial glucose levels.  

Pharmacokinetics:

• Acarbose degraded by intestinal amylases & bacteria
• Less than 2% absorbed & eliminated in urine
• Miglitol is completely absorbed & Eliminated in urine.

Indications & Contraindications:

Indications:

• Monotherapy for T2 DM with post-prandial hyperglycemia
• Add on therapy
• To extend post-prandial period to reduce interprandial glycemic troughs & hypoglycemia in pts taking sulphonylureas and/or Insulins.
• Prevent progression of IGT to T2 DM (Acarbose)

Contraindications:

• Chronic Intestinal Disease ( Gastrointestinal symptoms)
• Hepatic dysfunction (Acarbose  Raises Liver enzyme concentrations)  

Efficacy:

• Effectiveness depends on dietary compliance.
• HbA1C reduction 0.5 – 1%
• No weight gain
• No Frank Hypoglycemia
• Reduce Post prandial hyperinsulinemia with combo
• Acarbose reduce major cardiac events like MI (?)

Adverse effects:

• 
  

  Gastrointestinal Side effects like flatulence, abdominal  discomfort , diarrhea

• 
  

  Hypoglycemia uncommon

• 
  

  Avoided in conjuction with gut motility affecting agents & cholestyramine.

Brands:

Acarbose:

Acarb 50
Abacus
Diabose

Miglitol:

Euglitol
Miglit
Mignar

Voglibose:

Prandial 0.2/0.3
Oglibo MD
PPG
Alfabose

Meglitinides / Glinides (Short Acting Prandial Insulin Releasers)

Introduction :

• Non  sulphonylurea  moiety  of  Glibenclamide Contains Benzamido Group
• Used in Type 2 Diabetes
• Prandial Insulin Releasers
• Two Agents – Repaglinide  & Nateglinide Introduced in 1998 & 2001 respectively.

Mode Of Action:

• Bind To Benzamido site on sulphonylurea receptor SUR 1 in plasma membrane of islet B-cells.
• Closure of K+ATP channel
• Membrane  depolarization
• Opens  Voltage  dependent L-type calcium Channels
• Insulin release by exocitosis

Pharmacokinetics:

Repaglinide (0.5-4 mg) 

Max - 16 mg 

Peak – 1 hr

Duration of Action :  4-6 hr

Elimination in Bile(90%)

Nateglinide (60-180mg)

Max – 540 mg

Duration of Action : 3-5 hr

Elimination in Urine (80%)

Indications & Contraindications :

• Non pharmacological measure failed to control
• Those who exhibit post-Prandial hyperglycemia with near normal fasting glycemia( 15-30 Min before meals )
• Individuals with irregular lifestyles(missed meals)
• Elderly patients(less hypoglycemia)
• Where  other agents contraindicated ( Mod renal impairment with metformin & sulphonylurea  can not be used)
• Combination with metformin or thiazolidinediones.

Efficacy :

• Reduce post Prandial Hyperglycemia
• Small reduction in fasting hyperglycemia
• HbA1C  reduction – 0.5-1.5%

Adverse Effects :

• Hypoglycemia
• Sensitivity reactions
• Weight  gain when monotherapy

Common Brand Names:

Repaglinide :

Eurepa (0.5-1-2)

Novonorm (0.5-1-2)

Regan (0.5-1-2)

Nateglinide:

Glinate

Natiz

Natelide

Natstar