SGLT2 INHIBITION: A NOVEL TREATMENT STRATEGY FOR TYPE 2 DIABETES MELLITUS.
Treatment of Diabetes Mellitus
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Transcript of Treatment of Diabetes Mellitus
Treatment of diabetes:
Life style modification
Insulin
Oral hypoglycemic agents
Life style modification
Diet control
Exercise
Smoking cessation
DIET CONTROL
All diabetic patients should be
on diet control .
Diet control is a must either the
patient is taking insulin or oral
therapy .
Over weight should be reduced.
Diet control should be tried
at first before the next step
[insulin or tablets]
especially in obese
patients, When diet fails
drugs are indicated .
DIET CONTROL
The diet for a diabetic patient is not so different from the healthy diets for the whole
population.
Simple sugars Carbohydrate [as sucrose], should be limited for
the diet of diabetic patients.
DIET CONTROL
Carbohydrate content should be in a fiber-rich diet [for example
fruits containing fibers as apples] .
..… because the fiber content of diet delays absorption of
carbohydrates avoiding the rapid elevation of blood glucose levels .
DIET CONTROL
Calories:
•Calories should be tailored to the need of the patient .
Diet should contain:
Carbohydrates → 50 - 55% Fat→ 30-35% Protein →10 - 15%
DIET CONTROL
Indication of Insulin
Type 1 diabetes
Unstable diabetes
Type 2 diabetes failed on SUs.
Pregnant diabetic patients
Surgery (all diabetic patients)
Diabetic coma
Oral hypoglycemic agents
Biguanides
Sulfonylureas
α- glucosidase inhibitors
Thiazolidinediones
Prandial glucose regulator
Biguanides
Biguanides are derivatives of the
antimalarial agent
Chloroguanide. Which is found to
have hypoglycemic action .
The most commonly used
member of biguanides is
Metformin [Cidophage].
Biguanides
Indication:
Type 2 diabetes failed on diet
Metformin can be given alone
or in combination with
sulfonylureas or Insulin
BiguanidesMode of action
Biguanides [Metformin] is an Antihyperglycemic and not
Hypoglycemic agent .It does not stimulate pancreas to
secrete insulin and does not cause hypoglycemia (as a side effect) even
in large doses .
Also it has no effect on secretion of Glucagon or Somatostatin .
BiguanidesMode of action:
Decreases the intestinal absorption of CHO
Increases glucose uptake (GLUT 4)
Increases glucose utilization (glycogensynthase)
Increases glycolysis via anaerobic pathway (lactic acidosis)
Biguanides
Pharmacokinetics:Metformin is well absorbed
from small intestine, stable, does not bind to plasma
proteins, excreted unchanged in urine .
Half life of Metformin is 1.5 - 4.5 hours, taken in three
doses with meals
Biguanides
Side effects:
occur in 20-25 % of patients .
include.. Diarrhea, abdominal discomfort, nausea, metallic
taste and decreased
absorption of vitamin B12 .
BiguanidesContraindications
Patients with renal or hepatic impairment .
Past history of lactic acidosis . Heart failure, Chronic lung
disease .
..These conditions predispose to increased lactate production which causes lactic acidosis
which is fatal .
SUs., have been discovered during
the 2nd. World war (sulfonamide).
SUs are drugs that used orally to
control blood glucose levels of
type 2 diabetes .
SULFONYLUREAS
SULFONYLUREASTypes:
First generation ,Chlorpropamide (Pamidin)Tolbutamide (Diamol)
Second generation,Gliclazide (Diamicron)Glibenclamide (Daonil)Glipizide (Minidiab)
Third generation,Glimepiride (Diabride)
(Amaryl)
SULFONYLUREAS
Mechanism of action:
Pancreatic effect
Extra-pancreatic effect
Pancreatic effect:
•Increase insulin release
from pancreas
•Suppress secretions of
Glucagon
SULFONYLUREAS
SULFONYLUREASExtra pancreatic effect:
Increases the number of insulin receptors
Increases post-receptor insulin sensitivity
Increases glucolysisIncreases glycogen storage
in muscle and liverDecreases the hepatic
output of glucose
SULFONYLUREASPharmacokinetics:
They are effectively absorbed from gastrointestinal tract.
Food can reduce the absorption of sulfonylurea.
Sulfonylureas are more effective when given 30 minutes before
eating.Plasma protein binding is high 90
– 99 % .. mainly bind to albumen.
SULFONYLUREASPharmacokinetics:
1st generation members have short half lives.
2nd generation is
administered once, twice or
several times daily.
3rd generation is
administered once daily.
SULFONYLUREASPharmacokinetics:
All sulfonylurea are metabolized by liver and their metabolites
are excreted in urine with about 20 % excreted unchanged.
Sulfonylurea should be administered with caution to patients with either renal or
hepatic insufficiency.
SULFONYLUREAS
Adverse Reactions : Very few adverse reactions [4 %] in
the first generation and rare in the 2nd and 3rd generation .
SUs may induce hypoglycemia especially in elderly patients with
impaired hepatic or renal functions-These cases of hypoglycemia are
treated by I/V glucose infusion .
SULFONYLUREAS
Adverse Reactions: First generation may induce
other side effects as …nausea and vomiting & dermatological
reactions …These side effects are fewer in
the 2nd generation and rare in the 3rd generation.
SULFONYLUREASDrug interactions:
Some drugs may enhance or suppress the actions of sulfonylureas Either by
affecting:Their metabolism and
excretion The concentration of free
sulfonylureas in plasma through competing them on
plasma proteins.
Drug – Drug interaction
NSAIDs
Salicylates
Sulfonamide
ß-blockers
Chloramphenicol
Diazepam
MAOI
Barbiturates
Thiazide and loop diuretics
Sympathomimetics
Corticosteroids
Oestrogen / Progesterone combinations
SULFONYLUREAS
Contraindications :
Type 1 DM
Pregnancy and Lactation .
Significant hepatic or renal
failure .
α Glucosidase Inhibititor
Acarbose (Glucobay)
Indicated for type 2
diabetesIn addition with diet
In addition with other
anti-diabetic therapies
Acarbose (Glucobay)
Mode of action:Poorly absorbed 1% (act
locally in G.I.T.)Inhibits α glucosidase, so
inhibits CHO degradationDose:
50mg to 100mg 3 times daily before meals
Acarbose (Glucobay)
Side effects:
Flatulence (77%)
Diarrhea
Abdominal pain (21%)
Decreased iron absorption
Thiazolidenedione
Rosiglitazone (Avandia)
Pioglitazone (Actos)
Thiazolidenedione
Mode of action:Insulin sensitizer (increase
insulin sensitivity in muscle, adipose tissue & liver)
They are not insulin
secretagogues (Not insulin
releasers)
ThiazolidenedioneDrawbacks:
They are not effective alone in case of severe insulin deficiency
and should be combined with sulfonylurea or metformin or
bothSide effects:
Hepatotoxicity weight gainDyslipidaemia (increases LDL)
Prandial glucose regulators (Meglitinide)
Example:Repaglinide, Novonorm
(NovoNordisk)Rational:
Fast acting, short duration non-sulfonylurea
Designed to minimize mealtime blood glucose peaks
Repaglinide, Novonorm
Mechanism of action:Stimulation of pancreatic
insulin release by closing ß-cells KATP channels
Very rapid onset of action and short duration (TMAX = 1
hour, metabolized by liver T1/2 = 70 minutes)
No hypoglycemic metabolites
Repaglinide, Novonorm
Clinical efficacy:Improves postprandial glycemia Less effective in decreasing
fasting blood glucose levels and HbA1C
drawbacks:Fails to provides a stable 24 hours
blood glucose controlComplicated dosage style (3-8
tablets/daily)How to adapt the dosage to the
meal volume?