Manal Hassan Bashihab, Pharmacy Practice Resident First Year Pharmacological Management Of Type 2...

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!