manal hassan bashihab, pharmacy practice resident first year pharmacological management of type 2...
TRANSCRIPT
Manal Hassan Bashihab, Pharmacy Practice Resident
First Year
Pharmacological Management Of Type
2 Diabetes
OUTLINES Introduction to Type 2 DM
Screening of asymptomatic individuals.
Prevalence of Type 2 DM in KSA
Carbohydrate Metabolism.
Risk factors for Type 2 DM
Diagnostic criteria for Type 2 DM
Signs and symptoms of Type 2 DM
Lifestyle modification.
Pharmacotherapy in Type 2 DM.
Currently available therapeutic options for Type 2 DM.
New medications for management of type 2 DM.
Diabetic complications and their preventive measures.
Measurement of quality Indicators
OUTLINES , cont’d
TYPE 2 DM - AN INTRODUCTION
Disorders of insulin action and secretion.
It is characterized by symptomatic glucose intolerance as well as alterations in lipid and protein metabolism.
Type 2 diabetes is the most common form of diabetes.
Type 2 diabetes is frequently undiagnosed for many years because hyperglycemia develops gradually and at earlier stages.
It is often not severe enough for the patient to notice any of the classic symptoms of diabetes.
Nevertheless, such patients are at increased risk of developing Macro-vascular and Micro-vascular complications.
TYPE 2 DM – AN INTRODUCTION - Cont’d
PREVALENCE OF
TYPE 2 DM IN KSA
Diseases Distribution In (KSA )
With The Year 2000
Diabetes is the leading disease that put a great pressure on the health system.
0 5 10 15 20 25 30
Epilepsy
Tuberculosis
Hepatitis
DU
Asthma
Hypertension
Hyperlipedemia
Diabetes
2000 Diabetics attending Diabetic Center KSU.
2000 Saudi diabetics
2000 Diabetics attending Diabetic Center KSU.
GENERAL MORTALITY IN SAUDI DIABETICS
Cancer6%
Others6%
CVA18%
IHD46%
MI18%
Cardiac arrest6%
70 %
44%
32%
24%
Normal
Over-wieght
Obese
OBESITY IN SAUDI ARABIA
2000 Diabetics attending Diabetic Center KSU.
DM FAMILY HISTORYIN SAUDI ARABIA:
+ve FAMILY HISTORY in
general population = 32%
+ve FAMILY HISTORY in
diabetic population = 38%
0
10
20
30
40
50
Nephropathy
Prevalence of Microvascular complications:Comparing data from Arab countries with data of the highest & lowest prevalence world wide in the year 2000.
Neuropathy Retinopathy
WHO report 2000.
Carbohydrate
Metabolism
CARBOHYDRATE METABOLISM
Homeostatic mechanisms maintain plasma glucose concentration between 55 - 140
mg/dL(3.1 to 7.8 mmol/L).
A minimum concentration of 40 - 60 mg/dL(2.2 to 3.3 mmol/L) is required to provide adequate fuel for (CNS), which uses
glucose as its primary energy source.
CNS: Central Nervous System.
Blood glucose concentration exceed the Re-absorptive capacity of the kidneys( 180 mg/dL ), glucose spills into the urine resulting in a loss of calories and water.
Muscle and fat use glucose as major source of energy, but these tissues require insulin for glucose uptake.
If glucose is unavailable, these tissues are able to use amino acids and fatty acids for fuel.
CARBOHYDRATE METABOLISM – Cont’d
Postprandial Glucose Metabolism in the Nondiabetic IndividualIn muscle, insulin promotes the uptake of
glucose and its storage as glycogen.
It also stimulate the uptake of amino acid and their
conversion to protein.
In adipose tissue, glucose is converted to free fatty
acids and stored as triglycerides.Insulin prevents a breakdown of these triglycerides to free fatty acids.
The liver doesn't require insulin for glucose transport, but insulin facilitates the
conversion of glucose to glycogen and free fatty acids.
Fasting Glucose Metabolism in Nondiabetic IndividualAs blood glucose concentrations drop toward normal during the fasting state, insulin release
is inhibited .
A number of counter regulatory hormonesthat promote an increase in blood sugar are released (e.g., glucagon, epinephrine,
growth hormone, glucocorticoides).
Several processes maintain a minimum blood
glucose concentration for the CNS.
CNS: Central Nervous System.
Glycogen in the liver glucose.
Amino acids are transported from muscle to liver glucose.
Uptake of glucose by insulin dependent tissues is diminished to conserve glucose for the brain.
Triglycerides are broken down into free fatty acids, which are used as alternative fuel sources.
Fasting Glucose Metabolism in Nondiabetic Individual – Cont’d
(5) Excess glucose accumulationin the circulation
(2) Resistance to action of insulin
(1) impaired Insulin
secretion
(4) Glucose output
HepaticPeripheral
(3) Glucoseutilization
(6) Hyperglycemia Stimulates the pancreas to produce more insulin
Pathogenesis
Insulin Resistance Syndrome
Overweight/Obesity - Inactivity.
Hypertension.
A first degree relative with DM
Previous Gestational DM
Coronary Heart Disease
Dyslipidemia
Previously identified impaired fasting glucose (IFG) OR impaired glucose tolerance (IGT).
RISK FACTORS FOR DIABETES INCLUDE:
DIAGNOSIS
CLINICAL PRESENTATION OF HYPERGLYCEMIA
Screening of asymptomatic individuals at high risk for Type 2 DM should be carried out on an opportunistic basis.
Screening should begin at age 40 years, and be considered at an earlierage (e.g. 30 years) if risk factors for diabetes are present.
Screening should be carried out every 3 years for those with normal glucose tolerance and annually for those with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).
SCREENING OF ASYMPTOMATIC INDIVIDUALS.
DIAGNOSTIC CRITERIA OF TYPE 2 DM
Casual plasma glucose > 200 mg/dl and symptoms of diabetes OR
Fasting Plasma Glucose (FPG) >126 mg/dl OR
Results of a 2-hour 75-g Oral Glucose
Tolerance Test (OGTT) > 200 mg/dl
(Non-Pregnant Adults)
Flowchart For The Diagnosis Of Diabetes MellitusNo typical symptomsCasual plasma glucose >11.1 mmol/lORFasting plasma glucose >7.0 mmol/lNO YES
Repeat FPG
FPG >7.0 mmol/l
YES
DM
NOGo tofigure 2
Typical symptoms and/or acute metabolic decompensationUnequivocal hyperglycemiaCasual PG >11.1 mmol/lORFPG >7.0 mmol/l
Flowchart For Individuals Suspected To Have Diabetes But Whose FPG <7.0 Mmol/L
FPG
< 6.0 mmol/l 6.1- 6.9 mmol/l
Oral GlucoseTolerance Test
2- hour post -challenge glucose
<7.8mmol/l
7.8 - 11.0mmol/l
>11.1mmol/l
ImpairedFastingGlycaemia
ImpairedGlucoseTolerance
DiabetesMellitus
NormalFastingGlucose
GOALS OF GLYCEMIC CONTROL FOR PEOPLE WITH DIABETES
BIOCHEMICAL
INDEXNormal Goal
Average Fasting Plasma Glucose OR Pre-prandial Glucose
<100( mg/dl
)
90 - 130
Average 2-hoursPostprandial Plasma Glucose
< 120( mg/dl
)< 180
Average Bedtime Glucose
< 140(mg/dl)
110 - 150
A1C (%) - SUSTAINED
4 - 6%< 7 %
(2)
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GOALS OF GLYCEMIC CONTROL FOR PEOPLE WITH DIABETES – Cont’d
Blood Pressure
Less than 130/80 mmHg
INDEXMg / dl mMol / L
LIPIDS
LDL< 100< 2.6
TG< 150 < 1.7
HDL - Men > 40> 1.1
HDL - Women> 50> 1.4Ad
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LDL: Low Denisty Lipoprotein HDL: High Denisty Lipoprotein
TG: Triglycerides.
The American Diabetes Association Diagnostic Criteria
for DM
Normal and Diabetic Plasma Glucose Levels in mg/dL (mmol/L) for the Oral glucose Tolerance
Test
Fasting½,1,1½ Hr2 hr
Normal< 100 (5.6)
< 200 (11)
< 140 (7.8)
Impaired Glucose Tolerance
< 126 (7.0)
> 200 (11)140-200(7.8-11)
Impaired Fasting Glucose
100-125(6.1-7.0)
Diabetes (Non Pregnant Adult)
> 126 (7.0)
> 200 (11)
> 200 (11)
LIFESTYLE MODIFICATION
LIFESTYLE MODIFICATION
Lifestyle modification is a cornerstone of diabetes management and comprises the following: Medical Nutrition Therapy physical activity and exercise avoidance of smoking and alcoholic beverages.
MNT and exercise prescription should be the initial therapy in: obese (BMI > 30.0) and overweight (BMI > 25.0) type 2 diabetic patients UNLESS they are SYMPTOMATIC or SEVERELY HYPERGLYCEMIC.
MNT should be individualized. Saturated fat intake should not exceed 10%, with carbohydrates 50-60% and Proteins 15-20% of total calorie intake.
Diet should include foods from each of the basic food groups.An EXERCISE PROGRAM TAILORED to suit the individual’s age, fitness, aptitude and interest should be prescribed.A PRE-EXERCISE EVALUATION to identify Macro-vascular, Micro-vascular andneurological complications is recommended.
Individuals with diabetes, especially those on insulin treatment, should receive specific EDUCATION on the prevention of exercise-induced hypoglycemia.
Individuals with diabetic neuropathy should avoid exercises associated with REPETITIVE FOOT TRAUMA.
Individuals with severe diabetic Proliferative Retinopathy should avoid activities that dramatically elevate blood pressure.
Individuals with diabetes should be discouragedfrom SMOKING.
Diabetic patients with poor glycemic control or Dislipidemic should be discouraged from CONSUMING ALCOHOL.
PHARMACOLOGICAL MANAGEMENT
OF TYPE 2DM
Lifestyle changes: Diet, Exercise, Smoking, Lipids
Single Oral Agent
Combination Oral Therapy
Oral Therapy Plus Insulin
Insulin
Insulin Plus Thiazolidinedione, Metformin, or Sulfonylurea
STEPPED-CARE APPROACH TO TREATING
TYPE 2 DIABETES MELLITUS
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INITIAL TREATMENT STRATEGY
• Mild or NO symptoms AND• Negative ketones AND• No acute concurrent illness
• FPG > 200 OR• Random > 300 ANDDoes not meet criteriafor mild or severe
• Marked hyperglycemia OR• Significant weight loss OR• Severe/significant symptoms OR• 2+ or greater ketonuria OR• DKA, hyperosmolar state OR• Severe intercurrent illness or surgery
Start MNT &Physical Activity
Start OralAnti-diabetic Therapy
Start InsulinImmediately
Initial Presentation(Based on presentation of the items listed within each box)
6 - 8 weekstarget not met
Considerations For Selecting Initial Oral hypoglycemic Therapy
A combination of two drugs of different classes may be used as initial pharmacotherapy when there is marked hyperglycemia or when MNT & physical activity alone have not resulted in an A1C of < 8.0% .
MNT: Medical Nutrition Therapy.
( A ) ORAL HYPOGLYCEMIC AGENTS
BIGUANIDES
GLINIDES
SULFONYLUREAS
THIAZOLIDINEDIONE
-GLUCOSADASE INHIBITORS:
SITES OF ACTION
HYPERGLYCEMIA
Glucose
Absorption
Impaired insulin secretion
Decreased Glucose Uptake
Increased
HGO
α-Glucosidase Inhibitor
Metformin
TZD’sGlinide
s
SU
BIGUANIES
Stop the liver from making extra sugar
when it is not
needed
BIGUANIDES
MECHANISM OF ACTION:
Not stimulate insulin release.
There is an evidence that Metformin can:
FPG by the gluco-neo-genesis and by hepatic glucose production.It seems to improve peripheral sensitivity to insulin: enhanced glucose disposal and clearance. decreased plasma insulin concentration.TG ( 10 -20 %) by long term therapy. Total cholesterol ( 5-10 % )HDL by small increments.Weight loss more likely to occur.
Stop the liver from making extra sugar
when it is not
needed
PHARMACOKINETICS:
ABSORPTION: From small intestine ( 50 – 60
%)
ELIMINATION: Kidney as un-metabolized
medication.
PLASMA T ½: 6.2 Hrs.
PLASMA PROTEIN BINDING: Not bound to plasma protein.
Stop the liver from making extra sugar
when it is not
needed
ADVERSE DRUG REACTIONS:
Stop the liver from making extra sugar
when it is not
needed
Diarrhea,
GI Disturbances,
Abdominal Discomfort,
Metallic Taste.
Lactic Acidosis.
CONTRAINDICATIONS AND PRECAUTIONS:
Renal impairment
(may accumulate GFR less than 60 ml/min)
Hepatic disease.
CHF.
History of lactic acidosisAlcohol intake.
Shock.
Surgery.
Aging.
Tittered to minimum effective dose.
Renal function to be monitored regularly
Monitor CrCl in patients over 80 years.
Stop the liver from making extra sugar
when it is not
needed
DRUG INTERACTIONS :Stop the
liver from making extra sugar
when it is not
needed
Alcohol potentiates the effect of Metformin on lactate metabolism.
Parenteral contrast studies (e.g., angiography) that use iodinated materials.
Dosage & Clinical Use:
500 – 850 mg TID with meals.
Slowly dose by 500 mg once or twice daily
initially followed by weekly increments of 500 mg
daily.
Not used in patients over 80 Y.O. unless normal Renal function.(CrCl is 60 ml/min).
Stop the liver from making extra sugar
when it is not
needed
CrCl : Creatinine Clearance.
Stop the liver from making extra sugar
when it is not
needed
Decrease liver glucose output. Improve insulin resistance. Decrease plasma insulin concentration Improve lipid profile. Increase weight loss. Rarely cause hypoglycemia when used alone.
METFORMIN HAS POTENTIAL ADVANTAGES:
GLINIDES
GlinidesHelp Your Pancreas
MakeExtra insulin
MEGLITINIDES ( GLINIDES )
MECHANISM OF ACTION:
Close ATP sensitive K+ channels in beta cells
lead to membrane depolarization Ca +2 influx insulin secretion.
GlinidesHelp Your
Pancreas MakeExtra insulin
K: Potassium
Ca: Calcium.
PHARMACOKINETICS
REPAGLINIDENATEGLINIDE
Absorption
Rapidly absorbed & excreted.
Rapidly absorbed.
T ½ 1 Hr1.5Hr.
Metabolism
Completely metabolized by the liver to inactive products.
Metabolized
by the liver
Excretion
90% is excreted in the feces and 8% is excreted in the urine.
75% excreted inthe urine and 10% in the feces.
PPB>98%.Highly protein bound (98%).
GlinidesHelp Your
Pancreas MakeExtra insulin
Hr: Hour.
ADVERSE DRUG REACTIONS: Mild hypoglycemia if intake not followed by food in individual with blood glucose within normal range. Weight gain 0.9 - 3 KG.
CONTRAINDICATIONS & PRECAUTIONS:Should not be given to people with type 1
DRUG INTERACTIONS:Enzyme Inducers : Anti-TB , Anti-EpilepticsEnzyme inhibitors: Azoles, Anti-fungal, MacrolidesGlinides
Help Your
Pancreas MakeExtra insulin
Anti-TB: Anti Tuberculosis.
REPAGLINIDE:
If A1C 8% starting dose = 0.5 mg with each meal.
If A1C 8% starting dose = 1-2 mg.Weekly tittered the dose by 1 mg Per Each Meal.Maximum Dose: 4 mg per dose or 16 mg per
day.
DOSAGE AND CLINICAL USE:
GlinidesHelp Your
Pancreas MakeExtra insulin
NETAGLINIDE: 60 or 120 mg TID
OMMITT The dose if you skipped the
meal.
ADD The dose if you add an extra
meal.
TITER The dose with caution in
patient with liver dysfunction.
ROLE:
GlinidesHelp Your
Pancreas MakeExtra insulin
Help Your
Pancreas Make Extra
insulin
SULFONYLUREAS
SULFONYLUREAS
FIRST GENERATION:Acetohexamide, chlorpropamide, tolazamide, and tolbutamide.
SECOND GENERATION:Glipizide, Gliburide, Gliclazide, and Glimepiride.
MECHANISM OF ACTION:
(A) - Stimulate insulin release from pancreas beta cells specific receptors Increase beta cell sensitivity to glucose.
(B) Extra-pancreatic effect ( Sulfonylureas can): NORMALIZE hepatic glucose production, REVERSE insulin resistance in peripheral tissues in type 2 DM. BUT failure of this effect in type 1 DM.
PHARMACOKINETICS OF ORAL SULONYLUREAS
All are highly protein binding 90 – 100%.Food does not impair the extent of absorption
but may delay the time to peak.TOLBUTAMIDE & GLIPIZIDE:More effectively when given 30 min before meal, rather than with meal. GLIBINCLAMIDE:Unlike Glipizide Food does NOT delay the rate or extent of absorption.
HALF LIFE :
Tolbutamide Chlorpropamid
e Acetohexamide Tolazamide
Average is 7 hrs( 4 - 25 hr )
36 Hr (urine) Acidification serum t ½ to 68.5 h
1.3 H (Parent compound)5 Hs ( Active metabolites )
7 hrs
Glipizide Glibenclamide Glimepiride Gliclazide
2 – 4 hrs 1.5 – 4 hrs 9 hrs 8 – 12 hrs
DURATION OF ACTION
Tolbutamide Chlorpropamid
e Acetohexamide Tolazamide
Shortest 6 - 12 Hr
Longest 24 – 72 H
Interm. 12 - 18HrInterm. 12 - 24Hr
Glipizide Glibenclamide Glimepiride Gliclazide
Interm. 12 - 24HrInterm. Up to 24 Hr
Interm. Up to 24 Hr
Interm. Up to 24 Hr
Pharmacokinetics:
INTERM: Intermediate .
METABOLISM
Tolbutamide Chlorpropamid
e Acetohexamide Tolazamide
Rapid and complete
80% metabolized liver
Principally metabolized to Active compoundFurther metabolism to inactive metabolites.
Metabolized to many compounds.
Glipizide Glibenclamide Glimepiride Gliclazide
Extensively metabolized
Completely metabolized by the liver
Completely metabolized by the liver
Metabolized in the liver
EXCRETION
Tolbutamide Chlorpropamid
e Acetohexamide Tolazamide
Metabolites Excreted in the urine
20% excreted unchanged ( 10-60%)urine alkalanization excretion 4 folds.
50% of metabolites Excreted.
All excreted in the urine
Glipizide Glibenclamide Glimepiride Gliclazide
Metabolites Eliminated by the kidney
50% of metabolites excreted by kidney And remaining via biliary tract.
Metabolites excreted in both feces and urine.
60-80% in the urine 20% in the feces
Hypoglycemia.
Weight gain.
GIT symptoms ( Nausea, Fullness, bloating).
Rare: Allergic dermatologic reactions,
Hepatotoxicity,
ADVERSE DRUG REACTIONS
SUHelp Your
Pancreas Make Extra
insulin
CONTRAINDICATIONS AND PRECAUTIONS:
Type 1 DM.
Pregnancy and lactation.
Severe hepatic or renal dysfunction.
Severe acute intercurrent illness or stress.
SUHelp Your
Pancreas Make Extra
insulin
DRUG INTERACTIONS:
SUHelp Your
Pancreas Make Extra
insulin
Antacids: Glyburide absorption due to gastric PH.
Chloramphenicol: Tolbutamide hepatic metabolism and t½ 2-3 fold.
Salicylates: may sulfonylurea activity through protein binding displacement or inhibition of active renal tubular secretion.
Rifampin: Tolbutamide and Glyburide metabolism.
GLITAZONES
TZD’sHelp body
Cells use Insulin better
THIAZOLIDINEDIONE
MECHANISM OF ACTION:
These drugs insulin resistance In MUSCLE and LIVER, which enhances glucose utilization and hepatic glucose output.
Because this group enhance the effect of insulin, insulin must be present for them to exert their clinical effect.
They bind to and activate a nuclear receptor (PPAR-γ )
That is present in many insulin sensitive tissues to regulates the transcription of insulin responsive- genes that influence glucose and lipid metabolism.
PPAR-γ: Peroximase Proliferator Activated Receptor Gamma .
Pharmacokinetics:
ROSIGLITAZONE PKaPIOGLITAZONE
Complete Absorpti
on Food does not alter absorption
3 - 4 HrsElem. T
½ 16 - 24 Hr
Extensively metabolized by CYP2c8
Metabolism
Mainly in the liver by CYP3C4 and CYP2C8
Less potent than Parent compound
Metabolites
2 active metabolites
2/3rd in urine 1/3rd feces as conjugated metabolites
Excretion
15-30% of the dose is recovered in the urine as metabolites.Reminder excreted in the bile ( feces) either as unchanged or metabolites.
ROSIGLITAZONEPIOGLITAZONE
ONSETOccurs 1 - 2 weeks Maximum effect may not be seen for 8 - 12 weeks.
RENAL FAILURE
Because mainly excreted via feces with small amounts excreted as metabolites in the urine no dose adjustments are required.
PPBAll are extensively bound to serum albumin.
TZD’sHelp body
Cells use Insulin better
ADVERSE DRUG REACTIONS:
HEMATOLOGY:
Small decrease in Hgb and Hct
Transient in Neutrophil counts occurred infrequently within first 4 - 8 weeks of therapy.
TZD’sHelp body
Cells use Insulin better
HGB: Hemoglobin .
HCT: Hematocrit.
ADVERSE DRUG REACTIONS – cont’d
Increase In plasma volume reported.
No CHF has been observedCaution is suggested when using this group in CHF
Mild to moderate edema in small number of patients.
CARDIOVASCULAR:TZDsHelp body
Cells use Insulin better
CHF: Congestive Heart Failure .
HEPATOTOXICITY:
Reversible elevation in transaminase
( ALT, AST) 3 times the normal values.
Enzyme elevation typically peaked
between the 3rd and 7th month of therapy.
TZD’sHelp body
Cells use Insulin better
ADVERSE DRUG REACTIONS – cont’d
ALT: Alanine Aminotransferase .
AST: Aspartate Aminotransferase .
• If initial ALT is > 2.5 times normal, do not start this medication
• Once TZD is started, monitor ALT periodically thereafter according to clinical judgment.
• If ALT is > 2.5 times normal during treatment, check weekly.
If rise persists or becomes 3 times > normal, discontinue TZD
FDA Requirements for LFT monitoring for (TZD’s):
CONTRAINDICATIONS AND PRECAUTIONS
Type 1 DM.
Preexisting hepatic Disease.
Severe CHF
Hypersensitivity to this group.
Drugs metabolized by CYP3A4
TZD’sHelp body
Cells use Insulin better
DRUG INTERACTIONS:
HEPATIC MICROSOMAL ENZYME:
Pioglitazone induce hepatic microsomal enzyme (CYP3A4)
Rosiglitazone does not appear to inhibit any of the major CYP enzymes.
And this is the underlying mechanism for their interactions with ESTROGEN and TERFENADINE ( level by 50 - 70 %) , and should be alert about other medications metabolized by this enzyme: CYCLOSPORINE TACROLIMUS
DOSAGE AND CLINICAL USE:
Greater hypoglycemic effect has been observed when
it is given as 2 divided doses rather than as single dose.
Typical dose is 4 mg QD or 2 mg BID, regardless of meal.Dose can be titrated up to 8 mg BID.
ROSIGLITAZONETZD’sHelp body
Cells use Insulin better
DOSE:15mg QD - starting dose.
Up to 45 mg.
PIOGLITAZONE
Alpha
Glucosidase
Inhibitors
Slow the
digestion of
starches
ALPHA GLUCOSIDASE INHIBITORS:
MECHANISM OF ACTION:
Reversibly inhibits variety of enzymes ( GLUCOSIDASES )
present in the BRUSH BORDER of mucosa of small intestine
that are responsible for breakdown of complex poly saccharides and
sucrose into absorbable monosaccharide ( Glucose ).
Reduction occurs only when the agents are taken with meal containing a
complex CHO. Slow the absorption of glucose into blood. Diminish the rise in postprandial blood glucose. The portion of CHO that remains undigested in
the jejunum is transported to the ileum thus prolonging the
intestinal digestion.
CHO: Carbohydrate .
DuodenumDuodenum30 cm30 cmDuodenumDuodenum30 cm30 cm
JejunJejunumum
120 cm120 cm
JejunJejunumum
120 cm120 cm
IleumIleum
130 cm130 cm
IleumIleum
130 cm130 cm
With With AcarboseAcarboseWith With AcarboseAcarbose
Acarbose Blocks Proximal Absorption
Normal absorption of CHO
DOSAGE AND CLINICAL USE:
DOSE:50 mg TID if the patient is less than 60 KG.100 mg TID over 60 KG.
Increase by 25 mg per meal every 1-2 months to the maximum of 200mg TID
( maximum response after 6 months ).
NOT AFFECT WEIGHT, NOT AFFECT LIPID PROFILE.
Slow the
digestion of
starches
PHARMACOKINETICS:
ACARBOSEMIGLITOL
ABSORPTION GITGIT Good
METABOLISM
GI Amylase To Inactive
Metabolites
Advantage of lacking
Hepatotoxicity
T ½ 2.8 Hr 2 Hr
ADVERSE DRUG REACTIONS:
GIT – MAINLY.Flatulence, diarrhea, abdominal pain.( Due to fermentation of unabsorbed CHO in small intestine).
HEPATOTOXICITY:Monitor LFT monthly in patient using more than 150 mg / day
Slow the
digestion of
starches
CONTRAINDICATIONS & PRECAUTIONS:
GIT CONDITIONS:Malabsorption, IBS, intestinal
obstruction.
LIVER DISEASE:Monitor Monthly, D/C If
increased.
HYPOGLYCEMIA:Should be titrated by glucose
because the drug limits the availability of
disaccharides and sucrose.Note: hypoglycemia limited to
patients with combination therapy.
Slow the
digestion of
starches
D/C: Discontinue .
DRUG INTERACTIONS:
Absorption diminished by:CHARCOAL, DIGESTIVE Enzyme
Preparations.
Slow the
digestion of
starches
(B)INCRETIN MIMETICS AND NON-INSULIN SYNTHETIC
ANALOGS
INCRETIN: hormone produced by the gastrointestinal tract in response to food intake and necessary for glucose homeostasis
INCRETIN MIMETICS: a class of agents used for managing type 2 diabetes that mimics the enhancement of glucose-dependent insulin secretion and other gluco-regulatory actions of naturally occurring Incretins
GLOSSARYAmylin Analog
Amylin Analog Pramlintide (Symlin)®
Synthetic analog of the beta-cell hormone Amylin.It is currently approved in the U.S. only as adjunctive therapy
with insulin.
Mechanism of Action:It is administered SC before meals and slows gastric emptying. Preventing an increase of Serum Glucagon after meal.Increasing the feeling of satiety, promote weight loss.
It decreases the A1C by 0.5 – 0.7 %.The major clinical side effects are GIT, approximately in 30% of treated patients ( nausea).
Amylin Analog
Pramlintide (Symlin)®
Symlin also associated with weight loss around 1 – 1.5 Kg over 6
month.
Dosage and Clinical Use:Empiric insulin dose reductions is
necessary to reduce the risk of hypoglycemic episodes.
60 mcg SC prior each meals , Max. 120 mcg in the abdomen
or thigh, prior major meals.
Incretin Mimetics
Incretin Mimetics
Exenatide (Byetta)®
Naturally occurring peptide produced by the L- Cells of the small intestine. Exenatide is synthetic Exendin -4 was approved for use in the
U.S. in 2005.
Mechanism of Action:Stimulation GLP-1 receptor in the pancreatic beta cell.Stimulation of the production of insulin .Inhibition of the release of glucagon after meals.Slowing the rate of gastric emptying .Appetite suppression and weight loss .
GLP-1: Glucagon - Like Peptide 1 Receptor Agonist.
Exenatide (Byetta)®
It lowers A1C by 0.5 – 1 % mainly by lowering postprandial glucose levels.Associated with an around 2-3 Kg weight loss over 6
month.
Associated with hypoglycemia.Majority of side effects 30-45% of treated patients
experiencing nausea, vomiting or diarrhea.
Incretin Mimetics
Incretin MimeticsExenatide (Byetta)®
Dosage and Clinical Use : Adjunctive therapy in Type 2 diabetes who are not adequately controlled despite therapy with
Metformin or sulfonylurea or the combination of Metformin and sulfonylurea.5 mcg SC twice daily , within 60 min before the
morning and evening meal.
A1C Weight
Disadvantages
Other Advantages
Metformin
1.5%Lactic
acidosis
TG 10-20% -
TC 5-10%Not Expensive.
Sulfonylureas
1.5%
2KgWeight gain Weight gain
Not Expensive
Repaglinide
1.5%Weight gainShort Duration
Acarbose 0.5-
0.8%
Expensive, 3 times dose
No effect on the body weight
TZD’s 0.5-
1.4%
Expensive,Weight gain
Improve lipid profile
Exenatide 0.5
– 1% 2-3 Kg
Injections, Expensive,Little experience
Weight loss
Pramlintide 0.5 – 0.7
%
1-1.5Kg
Some Anti-diabetic Interventions SummarySome Anti-diabetic Interventions Summary
Metformin Efficacy:
A1c by 1.5% to 1.7% FPG by 50 -70 mg/dL
Efficacy of Repaglinide
FBG to 61 mg/dL.
PPG to 48 mg/dL.
A1c by 1.7%.
Efficacy - SU A1c by 1.5 - 1.7 % FPG by 50 - 70 mg/dL
Efficacy: alpha-Efficacy: alpha-GlucosidaseGlucosidase(PPG) by 25 to 50 mg/dL(PPG) by 25 to 50 mg/dL(FPG) by 20 to 30 mg/dL(FPG) by 20 to 30 mg/dLA1c by 0.5% to 1%A1c by 0.5% to 1%
TZD’s Efficacy when combined
with ;(SU) A1c = 0.9% - 1.3%(Metformin) A1c = 0.8% -
1.2%(Insulin) A1c = 0.6% - 1.0%
COM
BINATI
ON
THER
APY
• Insulin Secretagogue + Metformin**
• Sulfonylurea + Alpha-Glucosidase Inhibitor
• Thiazolidinediones + Sulfonylurea**
• Thiazolidinediones + Metformin**
• Thiazolidinediones + Repaglinide
• Sulfonylurea + Exenatide
• Metformin + Exenatide
SUGGESTED WELL-STUDIED COMBINATION THERAPY:
Glipizide / Metformin (Metaglib)® 2.5/250 mg, 2.5/500 mg, 5/500 mg.
Glyburide / Metformin (Glucovance)®
1.25/500 mg, 2.5/500mg, 5/500 mg.
Metformin / Rosiglitazone (Avandamet) ®
500/1mg, 500/2 mg, 500/4 mg
COMBINATION THERAPY OF INSULIN WITH ORAL AGENTS
COMBINATION THERAPY OF INSULIN WITH ORAL AGENTS
In type 2 diabetes, management using oral agents should be combined, or replaced, with insulin therapy depending on disease progression and development of secondary failure of oral agents.
Decisions to introduce insulin therapy to type 2 diabetic patients are often predicated on their inability to achieve target HbA1c levels after a duration of about 6 months or so, despite good compliance with optimal oral anti-diabetic regimens coupled with weight control and exercise programs.
COMBINATION THERAPY OF INSULIN WITH ORAL AGENTS
This may be initiated as a bedtime dose of intermediate or long acting or insulin with maintenance of oral agents during the day, an approach frequently termed bedtime insulin and daytime sulfonylurea or BIDS for short.
In patients with satisfactory fasting and pre-meal blood glucose levels but elevated post-dinner or bedtime readings,using premixed regular and intermediate-acting insulin pre-dinner may prove more effective than intermediate-acting insulin at bedtime.
THE ADVANTAGES OF BIDS INCLUDE:
Improved glycemic control with a smaller dose of insulin and therefore
Less weight gain than pure insulin therapy.
When glycemic control is not achieved despite BIDS regimen,discontinuing Sulfonylurea and switching to basal-bolus insulin regimen becomes necessary.
However, Metformin and Thiazolidinediones or α-Glucosidase inhibitors may still be used in conjunction with exogenous insulin to attenuate the insulin dose.
Fine-tuning of insulin doses is bestdetermined by home blood glucose monitoring.
Type 2 diabetes subjects who are switched to insulin temporarily during episodes of acute stress, such as sepsis, may be put back on oral agents when their glycemic control improves with declining insulin resistance and gluco-toxicity.
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5Treating Type 2 Diabetes Under Special Situations
Patient situation Consider Avoid
Renal Function
Glipizide GlimepirideTolazamideINSULINTZD’sRepaglinides
AcarboseMetforminAcetohexamide
Liver FunctionInsulin RepaglinideMiglitol
AcarboseMetforminAcetohexamideTZD’s
HyperlipidemiaMetformin TZD’s
Obesity Acarbose Miglitol Metformin
InsulinSURepaglanide
Hypoglycemia due to irregular eating patterns
Metformin AcarboseRepaglinide TZD’s
Insulin Long acting SU
CHRONIC DIABETIC COMPLICATIONS
The Risk Of Serious Complications Is Increased Dramatically In Diabetes Mellitus
ComplicationRelative
Risk
Blindness20 X
End-stage Renal disease
25 X
Amputation40 X
Myocardial Myocardial
2 - 5 %
Stroke2 - 3 %
Biology of Microvascular Complications:
Eye Kidn
ey Nerv
es
Retinopathy
Cataract Glaucoma
NephropathyMicroalbuminu
ria Gross albuminuria
Neuropathy Peripheral Autonomic
Blindness
Kidney Failure
Amputation
Death OR
Diasbility
Biology of Macrovascular Complications:
Heart
BrainExtremiti
es
Coronary Artery Disease
Cerebrovascular
Disease
Peripheral Vascular Disease
Heart attacks Heart
Failure
Stroke Cognitive impairme
nt
Ulceratio
nGangren
e Amputati
on
MEASUREMENT OF
QUALITY INDICATORS
Measurement of quality IndicatorsQuality Indicator Recommended Frequency
HbA1cAt risk: 6 monthlyHigh risk: 3-4 month
Eye assessmentAt risk: annual High risk:
as clinically indicated
Foot assessmentAt risk: annualHigh risk: as clinically indicated
Nephropathy assessment
At risk: annual High risk: as clinically indicated
Blood pressureAt risk: 3-4 month High risk: as clinically indicated
Weight and BMIAt risk: 3-4 month High risk: as clinically indicated
Lipid profileAt risk: annual High risk: as clinically indicated
Cardiac assessmentAt risk: as clinically indicated
High risk: as clinically indicated
Self-management education
At risk: annual High risk: as clinically indicated
SUMMARY
Diabetes is more than a glucose issue!
Empower the person with diabetes
Think PREVENTION!
Screen early
Treat aggressively
Knowing is not enoughwe must APPLY !
Willing is not enough We must DO!