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are phenformin & buformin (which were withdrawn due to lactic acidosis)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

 

Etiologic classification of Diabetes Mellitus :

Etiologic classification of DM  :

• Type 1 Diabetes 

1.   Immune Mediated
2.    Idiopathic

• Type 2 Diabetes
• Gestational  Diabetes Mellitus
• Others:

1. Genetic defects of β-cell function ( MODY 3,1,2, TND )
2. Genetic defects in insulin action  (Leprechaunism,Rabson–Mendenhall sd)
3. Diseases of the exocrine pancreas (Pancreatitis, Trauma , Neoplasia, CF)
4. Endocrinopathies (Acromegaly, Cushing’s, Hyperthyroidism ,Pheochromo..)
5. Drug or chemical induced ( Vacor, Glucocorticoids, Thiazides)
6. Infections (Congenital rubella, CMV )
7. Uncommon forms of immune-mediated diabetes (Stiff-man syndrome)
8. Other genetic syndromes sometimes associated with diabetes ( XO, XXY, Trisomy 21, etc)

Diabetes Mellitus - Introduction & Definition

History :

• The term "diabetes" was first coined by Araetus of Cappodocia (81-133AD)
• Later, the word mellitus (honey sweet) was added by Thomas Willis (Britain) in 1675 after rediscovering the sweetness of urine and blood of patients (first noticed by the ancient Indians).
• 1776 that Dobson (Britain) firstly confirmed the presence of excess sugar in urine and blood as a cause of their sweetness. 
• the concept that diabetes is due to excess glucose production Claude Bernard (France) in 1857
• The role of the pancreas in pathogenesis of diabetes was discovered by Mering and Minkowski (Austria) 1889.
• basis of insulin isolation and clinical use by Banting and Best (Canada) in 1921
• 1955 First OHA Tolbutamide & carbutamide Marketed

Brief :

Diabetes mellitus is a group of metabolic diseases in which a person has high blood sugar, either because the pancreas does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of 

-polyuria (frequent urination), 

-polydipsia (increased thirst), and 

-polyphagia (increased hunger).

Standard Definition:

Diabetes Mellitus is a heterogeneous chronic metabolic disorder principally characterized by persistent hyperglycemia resulting from defects in insulin action and/or insulin secretion.