Management of Diabetes Mellitus

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DIABETES MELLITUS TYPE IIDIABETES MELLITUS TYPE II

Yasser GebrilYasser GebrilInpatient PharmacyInpatient Pharmacy

1.1. Insulin ResistanceInsulin Resistance

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NIDDM (TYPE II DM)NIDDM (TYPE II DM)

• Serious and chronic disease.Serious and chronic disease.• Progressive condition.Progressive condition.• Associated with a number of chronic Associated with a number of chronic

complications.complications.• Macrovascular complications:Macrovascular complications:

– Cardiovascular disease (CVD)Cardiovascular disease (CVD)

• Microvascular complications:Microvascular complications:– NephropathyNephropathy– RetinopathyRetinopathy– NeuropathyNeuropathy

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FEATURES OF TYPE I AND TYPE FEATURES OF TYPE I AND TYPE II DMII DMCharacteristicCharacteristic Type IType I Type IIType IIOnset (age)Onset (age) Usually <30Usually <30 Usually >40Usually >40

Type of onsetType of onset AbruptAbrupt GradualGradual

Nutrition StatusNutrition Status Often ThinOften Thin Often ObeseOften Obese

Clinical SymptomsClinical Symptoms Polydipsia, polyurea, polyphagiaPolydipsia, polyurea, polyphagia Often a symptomaticOften a symptomatic

KetosisKetosis PresentPresent Usually absentUsually absent

Endogenous insulinEndogenous insulin AbsentAbsent VariableVariable

Insulin therapyInsulin therapy RequiredRequired SometimesSometimes

Oral hypoglycemicsOral hypoglycemics Usually not effectiveUsually not effective Often effectiveOften effective

DietDiet Mandatory with insulinMandatory with insulin Mandatory with or without Mandatory with or without drugsdrugs

Curtis L. Triplitt, Charles A. Reasner, and William L. Isley -Pharmacotherapy

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DIAGNOSIS OF DMDIAGNOSIS OF DM

• Diagnosis of diabetes is made by Diagnosis of diabetes is made by three criteria:three criteria:– fasting plasma glucose ≥126 mg/dL,fasting plasma glucose ≥126 mg/dL,– A 2-hour value from a 75-g oral A 2-hour value from a 75-g oral

glucose tolerance test ≥200 mg/dL,glucose tolerance test ≥200 mg/dL,– Or a casual plasma glucose level of Or a casual plasma glucose level of

≥200 mg/dL with symptoms of ≥200 mg/dL with symptoms of diabetes.diabetes.

• with results confirmed by any of with results confirmed by any of the three criteria on a separate the three criteria on a separate day.day.

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PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF NIDDMNIDDM

• It is based on two main metabolic It is based on two main metabolic abnormalities:abnormalities:– Insulin resistance.Insulin resistance.– Impaired pancreatic Impaired pancreatic -cell function.-cell function.

• Studies in the earliest phase of pre-Studies in the earliest phase of pre-diabetes have shown that insulin diabetes have shown that insulin resistance is the predominant early resistance is the predominant early abnormality, even in lean individuals abnormality, even in lean individuals who later progress to type 2 DM.who later progress to type 2 DM.

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• Minute defects in pancreatic Minute defects in pancreatic -cell -cell function become evident once IGT function become evident once IGT begins and are characterized by:begins and are characterized by:– Blunted early phase insulin secretion Blunted early phase insulin secretion

andand– Late hyperinsulinemic response.Late hyperinsulinemic response.

• Once diabetes is established, insulin Once diabetes is established, insulin secretion is more disrupted:secretion is more disrupted:– There is almost complete loss of the There is almost complete loss of the

early phase insulin response.early phase insulin response.– Blunted late response to glucose or Blunted late response to glucose or

meals.meals.

PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF NIDDMNIDDM

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• The cellular and molecular The cellular and molecular mechanism of insulin resistance and mechanism of insulin resistance and -cell dysfunction remain -cell dysfunction remain incompletely understood.incompletely understood.

• However, the pathologies of these two However, the pathologies of these two defects appear to be interlinked.defects appear to be interlinked.

• Possibly through adverse effects of Possibly through adverse effects of hyperglycemia (glucotoxicity) and/or hyperglycemia (glucotoxicity) and/or elevated FFA (lipotoxicity) on insulin elevated FFA (lipotoxicity) on insulin sensitivity and sensitivity and -cell function.-cell function.

PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF NIDDMNIDDM

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PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF NIDDMNIDDM• Because the incidence of diabetes is Because the incidence of diabetes is

high in families of persons with high in families of persons with NIDDM, a strong genetic NIDDM, a strong genetic predisposition is suspectedpredisposition is suspected

• The three major metabolic The three major metabolic abnormalities in NIDDM are:abnormalities in NIDDM are:– Defective glucose-induced insulin Defective glucose-induced insulin

secretionsecretion– Increased hepatic glucose outputIncreased hepatic glucose output– Inability of insulin to stimulate glucose Inability of insulin to stimulate glucose

uptake by peripheral target tissues.uptake by peripheral target tissues.• Another essential problem in NIDDM Another essential problem in NIDDM

may be reduced Insulin Sensitivity of may be reduced Insulin Sensitivity of fat and muscle cells to the effects of fat and muscle cells to the effects of insulin (insulin resistance)insulin (insulin resistance)

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DEVELOPMENT OF TYPE 2 DEVELOPMENT OF TYPE 2 DIABETESDIABETES

Fasting Fasting glucoseglucose

Glucose Glucose tolerancetolerance

Insulin Insulin sensitivitysensitivity

InsulinInsulinsecretiosecretio

nn

HyperglycemiaHyperglycemia

AbnormalAbnormalglucose toleranceglucose tolerance

Decreased insulinDecreased insulinsensitivitysensitivity

Hyperinsulinemia,Hyperinsulinemia,then then -cell failure-cell failure

NormalNormal IGTIGT Type 2 Type 2 diabetes diabetes

II IIII IIIIII IVIV VV

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THE UKPDS DEMONSTRATED THAT THE UKPDS DEMONSTRATED THAT LOSS OF GLYCEMIC CONTROL LOSS OF GLYCEMIC CONTROL CORRELATES WITH PROGRESSIVE CORRELATES WITH PROGRESSIVE LOSS OF LOSS OF -CELL FUNCTION-CELL FUNCTION

UK Prospective Diabetes Study Group. Diabetes 1995; 44:1249–1258.

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NORMAL INSULIN NORMAL INSULIN ACTIONACTION• In the fasting state 75% of total body In the fasting state 75% of total body

glucose disposal takes place the brain glucose disposal takes place the brain and splanchnic tissues (liver and GIT and splanchnic tissues (liver and GIT Tissues).Tissues).

• Brain glucose is not altered in NIDDM.Brain glucose is not altered in NIDDM.• The remaining 25% of glucose The remaining 25% of glucose

metabolism takes place in muscle, which metabolism takes place in muscle, which is dependent on insulin.is dependent on insulin.

• In the fasting state approximately 85% of In the fasting state approximately 85% of glucose production is derived from the glucose production is derived from the liver.liver.

• In the fed state, carbohydrate ingestion In the fed state, carbohydrate ingestion increases the plasma glucose increases the plasma glucose concentration and stimulates insulin concentration and stimulates insulin release from the pancreatic release from the pancreatic β β cells.cells.

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NORMAL INSULIN NORMAL INSULIN ACTIONACTION• The resultant hyperinsulinemia has The resultant hyperinsulinemia has

two actions:two actions:1.1. suppresses hepatic glucose productionsuppresses hepatic glucose production2.2. stimulates glucose uptake by stimulates glucose uptake by

peripheral tissues.peripheral tissues.

• The majority (80% to 85%) of The majority (80% to 85%) of glucose that is taken up by glucose that is taken up by peripheral tissues is disposed of in peripheral tissues is disposed of in muscle, with only a small amount muscle, with only a small amount (4% to 5%) being metabolized by (4% to 5%) being metabolized by adipocytes.adipocytes.

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NORMAL INSULIN NORMAL INSULIN ACTIONACTION• Although fat tissue is responsible for Although fat tissue is responsible for

only a small amount of total body only a small amount of total body glucose disposal, it plays a very glucose disposal, it plays a very important role in the maintenance of important role in the maintenance of total body glucose homeostasis. total body glucose homeostasis.

• The decline in plasma FFA The decline in plasma FFA concentration results in increased concentration results in increased glucose uptake in muscle, and reduces glucose uptake in muscle, and reduces hepatic glucose production.hepatic glucose production.

• Thus a decrease in the plasma FFA Thus a decrease in the plasma FFA concentration lowers plasma glucose by concentration lowers plasma glucose by both decreasing its production and both decreasing its production and enhancing the uptake in muscleenhancing the uptake in muscle

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11- - AssociationAssociation

22- Signal- Signal

Glucose Transpor

ters

33- - TranslocatioTranslocationn

55- - FusionFusion

44- - BindingBinding

GlucoseGlucose

66- - TransportTransport

77- Dissociation- Dissociation

88- - TranslocatioTranslocationn

TRANSLUCATION TRANSLUCATION OF GLUCOSE OF GLUCOSE TRANSPORTERS TRANSPORTERS BY INSULINBY INSULIN

Kernili Et al; Insulin Stimulated Translocation of Glucose Transporters in the isolated rat adipose cell.

J. Biol. Chem. 1981; 256:4772

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INSULIN INSULIN RESISTANCERESISTANCE• Definition: Definition:

– A defective binding of insulin to a receptor and A defective binding of insulin to a receptor and blunting of insulin signal transductionblunting of insulin signal transduction

• Conditions associated with elevated insulin Conditions associated with elevated insulin levels levels (Hyperinsulinism)(Hyperinsulinism), such as obesity, , such as obesity, may be the result of down-regulation in the may be the result of down-regulation in the number of insulin receptors, effectively number of insulin receptors, effectively resulting in a state of insulin resistance.resulting in a state of insulin resistance.

• Conversely, decrease in insulin levels, (e.g. Conversely, decrease in insulin levels, (e.g. diabetes) may lead to an up-regulation of diabetes) may lead to an up-regulation of the receptors, which may shift the insulin the receptors, which may shift the insulin dose-response curve; that is less insulin dose-response curve; that is less insulin would be required to produce a given would be required to produce a given biological effectbiological effect

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INSULIN INSULIN RESISTANCERESISTANCE• IR has been associated with a IR has been associated with a

number of hormonal and metabolic number of hormonal and metabolic states, including:states, including:– Cushing’s syndrome (excessive Cushing’s syndrome (excessive

corticosteroids)corticosteroids)– Acromegaly (Excessive growth Acromegaly (Excessive growth

hormone) and hormone) and – Gestational diabetesGestational diabetes

• Physiological or psychological stress Physiological or psychological stress also can contribute to insulin also can contribute to insulin resistance.resistance.

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METABOLIC METABOLIC SYNDROMESYNDROME• Patients are said to have metabolic Patients are said to have metabolic

syndrome if they show three or more of syndrome if they show three or more of the following:the following:– Abdominal obesityAbdominal obesity– Atherogenic dyslipidemiaAtherogenic dyslipidemia– Raised blood pressureRaised blood pressure– Insulin resistance with or without glucose Insulin resistance with or without glucose

intoleranceintolerance• Associated with obesity is a sedentary Associated with obesity is a sedentary

lifestyle, and inactivity; that may lifestyle, and inactivity; that may contribute to higher blood pressure, contribute to higher blood pressure, elevated blood lipid levels, and insulin elevated blood lipid levels, and insulin resistance associated with glucose resistance associated with glucose intolerance (insulin resistance intolerance (insulin resistance syndrome).syndrome).

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ROLE OF FREE FATTY ACIDS IN THE ROLE OF FREE FATTY ACIDS IN THE PATHO-GENESIS OF TYPE 2 DIABETESPATHO-GENESIS OF TYPE 2 DIABETES

HyperglycemiaHyperglycemia

ElevateElevatedd

plasma plasma FFAFFALarge insulin resistant Large insulin resistant

adipocytesadipocytesReduced suppression of Reduced suppression of lipolysislipolysis

Increased glucoseIncreased glucoseoutputoutput

LipotoxicityLipotoxicityInhibition of Inhibition of -cell -cell

function function

Reduced glucose Reduced glucose uptakeuptake

Reduced insulin Reduced insulin secretionsecretion

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Increased Increased lipolysislipolysis

Decreased glucose Decreased glucose uptake into muscle uptake into muscle and adipose tissue and adipose tissue and raised hepatic and raised hepatic

glucose output glucose output

HyperglycemiaHyperglycemia

Insulin resistanceInsulin resistance

-cell dysfunction-cell dysfunction

High insulin demand High insulin demand and insulin and insulin

resistance in resistance in pancreaspancreas

Elevated circulating FFAElevated circulating FFA

gluco

toxic

ity

gluco

toxic

itylipotoxicity

lipotoxicity

ELEVATED CIRCULATING FFA IS A CENTRAL FACTOR IN THE DEVELOPMENT OF TYPE 2 DIABETES

Arner P. Arner P. Diabetes Obes Met Diabetes Obes Met 2001;3 (Suppl.1); S11–S19. 2001;3 (Suppl.1); S11–S19.

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IMPAIRED INSULIN IMPAIRED INSULIN SECRETIONSECRETION• The pancreas in people with a normal The pancreas in people with a normal

functioning functioning β β cell is able to adjust its cell is able to adjust its secretion of insulin to maintain normal secretion of insulin to maintain normal glucose tolerance.glucose tolerance.

• Thus in non-diabetic individuals, insulin is Thus in non-diabetic individuals, insulin is increased in proportion to the severity of increased in proportion to the severity of the insulin resistance and glucose tolerance the insulin resistance and glucose tolerance remains normal.remains normal.

• Impaired insulin secretion is a uniform Impaired insulin secretion is a uniform finding in type 2 diabetic patients and the finding in type 2 diabetic patients and the evolution of evolution of ββ-cell dysfunction has been -cell dysfunction has been well characterized in diverse ethnic well characterized in diverse ethnic populations.populations.

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IMPAIRED INSULIN IMPAIRED INSULIN SECRETIONSECRETION• DeFronzo and colleagues measured the fasting DeFronzo and colleagues measured the fasting

plasma insulin concentration and performed oral plasma insulin concentration and performed oral glucose tolerance tests in 77 normal weight type glucose tolerance tests in 77 normal weight type 2 diabetic patients and over 100 lean subjects 2 diabetic patients and over 100 lean subjects with normal or impaired glucose tolerance.with normal or impaired glucose tolerance.

• The relationship between the fasting plasma The relationship between the fasting plasma glucose concentration and the fasting plasma glucose concentration and the fasting plasma insulin concentration resembles an inverted U or insulin concentration resembles an inverted U or horseshoe.horseshoe.

• As the fasting plasma glucose concentration rises As the fasting plasma glucose concentration rises from 80 to 140 mg/dL, the fasting plasma insulin from 80 to 140 mg/dL, the fasting plasma insulin concentration increases progressively, peaking concentration increases progressively, peaking at a value that is 2- to 2.5-fold greater than in at a value that is 2- to 2.5-fold greater than in normal weight non-diabetic controls. When the normal weight non-diabetic controls. When the fasting plasma glucose concentration increases fasting plasma glucose concentration increases over 150 mg/dL insulin secretion in reduced.over 150 mg/dL insulin secretion in reduced.

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THE RELATIONSHIP THE RELATIONSHIP BETWEEN FASTING PLASMA BETWEEN FASTING PLASMA INSULIN AND FASTING INSULIN AND FASTING PLASMA GLUCOSEPLASMA GLUCOSE

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DEVELOPMENT OF TYPE 2 DEVELOPMENT OF TYPE 2 DIABETESDIABETES

Fasting Fasting glucoseglucose

Glucose Glucose tolerancetolerance

Insulin Insulin sensitivitysensitivity

InsulinInsulinsecretiosecretio

nn

HyperglycemiaHyperglycemia

AbnormalAbnormalglucose toleranceglucose tolerance

Decreased insulinDecreased insulinsensitivitysensitivity

Hyperinsulinemia,Hyperinsulinemia,then then -cell failure-cell failure

NormalNormal IGTIGT Type 2 Type 2 diabetes diabetes

II IIII IIIIII IVIV VV

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SITE OF INSULIN SITE OF INSULIN RESISTANCE IN TYPE 2 RESISTANCE IN TYPE 2 DIABETESDIABETES• Liver

– Resulting in increased Glucose output (gluconeogenesis)

• Peripheral Muscles– Reduced uptake by Muscles,

increased output (glyconenolysis)• Peripheral Adipocyte

– Reduced uptake by adipocytes, increased output (Lipolysis)

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GOALS OF THERAPYGOALS OF THERAPY

• Reducing symptoms of Reducing symptoms of hyperglycemia.hyperglycemia.

• Reducing the onset and progression Reducing the onset and progression of retinopathy, nephropathy, and of retinopathy, nephropathy, and neuropathy complications.neuropathy complications.

• Intensive therapy for associated Intensive therapy for associated cardiovascular risk factors.cardiovascular risk factors.

• Improving quality and quantity of Improving quality and quantity of lifelife

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TREATMENT OF IRTREATMENT OF IR

• MetforminMetformin• ThiazolidinedionesThiazolidinediones

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METFORMINMETFORMIN

• Metformin should be included in the Metformin should be included in the therapy for all type 2 DM patients, if therapy for all type 2 DM patients, if tolerated and not contraindicated, tolerated and not contraindicated, as it is the only oral anti-as it is the only oral anti-hyperglycemic medication proven to hyperglycemic medication proven to reduce the risk of total mortality reduce the risk of total mortality and cardiovascular death, according and cardiovascular death, according to the United Kingdom Prospective to the United Kingdom Prospective Diabetes Study.Diabetes Study.

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PHARMACOLOGYPHARMACOLOGY

• Metformin enhances insulin Metformin enhances insulin sensitivity of both hepatic and sensitivity of both hepatic and peripheral (muscle) tissues.peripheral (muscle) tissues.

• This allows for an increased This allows for an increased uptake of glucose into these uptake of glucose into these insulin-sensitive tissues.insulin-sensitive tissues.

• Reduction of carbohydrate Reduction of carbohydrate absorption from GITabsorption from GIT

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PHARMACOKINETICSPHARMACOKINETICS

• Metformin has approximately 50% to 60% oral bioavailability, low lipid solubility, and a volume of distribution that approximates body water.

• Metformin is not metabolized and does not bind to plasma proteins.

• Metformin is eliminated by renal tubular secretion and glomerular filtration. The average half-life of metformin is 6 hours, though pharmacodynamically, metformin’s antihyperglycemic effects last >24 hours.

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EFFICACY OF EFFICACY OF METFORMINMETFORMIN• Metformin consistently reduces HbA1c

levels by 1.5% to 2.0%, fasting plasma glucose levels by 60 to 80 mg/dL, and retains the ability to reduce fasting plasma glucose levels when they are extremely high (>300 mg/dL).

• Metformin also has positive effects on several components of the insulin resistance syndrome.

• Metformin decreases plasma triglycerides and LDL-C by approximately 8% to 15%, as well increasing HDL-C very modestly (2%).

• Metformin reduces levels of plasminogen activ-ator inhibitor-1 and causes a modest reduction in weight (2 to 3 kg).

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EFFICACY CONT…EFFICACY CONT…

• Metformin reduced macro-vascular Metformin reduced macro-vascular complicati-ons in obese subjects in the complicati-ons in obese subjects in the UKPDS.UKPDS.

• Metformin significantly reduced all-Metformin significantly reduced all-cause mort-ality and risk of stroke vs. cause mort-ality and risk of stroke vs. intensive treatment with sulfonylureas intensive treatment with sulfonylureas or insulin.or insulin.

• Metformin also reduced diabetes-Metformin also reduced diabetes-related death and myocardial related death and myocardial infarctions vs. the conventional infarctions vs. the conventional treatment arm of the UKPDS.treatment arm of the UKPDS.

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ADVERSE EFFECTSADVERSE EFFECTS• Gastrointestinal side effects, including Gastrointestinal side effects, including

abdominal discomfort, stomach upset, and/or abdominal discomfort, stomach upset, and/or diarrhea in approximately 30% of patients.diarrhea in approximately 30% of patients.

• Anorexia and stomach fullness is likely part Anorexia and stomach fullness is likely part of the reason loss of weight is noted with of the reason loss of weight is noted with metformin.metformin.

• These side effects are usually mild and can These side effects are usually mild and can be minimized by slow titration.be minimized by slow titration.

• Metallic tasteMetallic taste• Interference with vitamin B12 absorptionInterference with vitamin B12 absorption• Hypoglycemia during intense exercise has Hypoglycemia during intense exercise has

been documented, but are clinically been documented, but are clinically uncommon.uncommon.

• Metformin therapy rarely causes lactic Metformin therapy rarely causes lactic acidosisacidosis

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CONTRAINDICATIONCONTRAINDICATIONSS• Any disease state that may increase Any disease state that may increase

lactic acid production or decrease lactic lactic acid production or decrease lactic acid removal may predispose to lactic acid removal may predispose to lactic acidosis. acidosis.

• Tissue hypo-perfusion, such as that due Tissue hypo-perfusion, such as that due to congestive heart failure, hypoxic to congestive heart failure, hypoxic states, shock, or septicemia,states, shock, or septicemia,

• Severe liver disease or alcohol Severe liver disease or alcohol consumption.consumption.

• renal insufficiencyrenal insufficiency• Elderly patientsElderly patients

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THIAZOLIDINEDIONESTHIAZOLIDINEDIONES

• Pioglitazone (Glustin - Actos)Pioglitazone (Glustin - Actos)• Rosiglitazone (Avandia)Rosiglitazone (Avandia)

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PHARMACOLOGYPHARMACOLOGY

• Thiazolidinediones work by Thiazolidinediones work by binding to the PPAR-binding to the PPAR-γγ, which are , which are primarily located on fat cells and primarily located on fat cells and vascular cells.vascular cells.

• Thiazolidinediones enhance Thiazolidinediones enhance insulin sensitivity at muscle, liver, insulin sensitivity at muscle, liver, and fat tissues indirectly.and fat tissues indirectly.

• Thiazolidinediones cause Thiazolidinediones cause preadipocytes to differentiate into preadipocytes to differentiate into mature fat cells in subcutaneous mature fat cells in subcutaneous fat stores.fat stores.

PPAR-γγ= peroxisome proliferator activator peroxisome proliferator activator receptor-receptor-γγ

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Nuclear receptor PPAR ( peroxisome proliferator activator receptor )

↓Transcription of glucose transporter gene

GLUT4↓

Increase in insulin mediated peripheral glucose uptake and utilization ( muscle,

adipose tissue )↓

Maximal effect reached after 3-6 weeks

MECHANISM OF ACTION MECHANISM OF ACTION OF THIAZOLIDINEDIONESOF THIAZOLIDINEDIONES

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InsulinInsulin

GutGut

CarbohydrateCarbohydrate

AdiposeAdiposetissuetissue

Blood Blood glucoseglucose

DigestiDigestiveveenzymeenzymessPancreasPancreas

MuscleMuscleLiverLiver

TZD EFFECTS AT TARGET TZD EFFECTS AT TARGET TISSUESTISSUES

Decreases Decreases excessive excessive hepatic hepatic glucoseglucoseproductioproductionn

Improves insulin-mediated glucose Improves insulin-mediated glucose uptakeuptake

Decreases Decreases excessive lipolysis excessive lipolysis and reduces free and reduces free fatty acidsfatty acids

Decreases Decreases plasma glucose plasma glucose levelslevels

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PHARMACOKINETICSPHARMACOKINETICS

• Pioglitazone and rosiglitazone are Pioglitazone and rosiglitazone are well absorbed with or without well absorbed with or without food. Both are highly (food. Both are highly (>>99%) 99%) protein bound to albumin.protein bound to albumin.

• The half-life of pioglitazone and The half-life of pioglitazone and rosiglitazone is 3 to 7 hours and 3 rosiglitazone is 3 to 7 hours and 3 to 4 hours, respectively.to 4 hours, respectively.

• Both medications have a duration Both medications have a duration of antihyperglycemic action of of antihyperglycemic action of over 24 hours.over 24 hours.

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EFFICACYEFFICACY• Pioglitazone and rosiglitazone, given for about Pioglitazone and rosiglitazone, given for about

6 months, reduce HbA1c values∼1.5% and 6 months, reduce HbA1c values∼1.5% and reduce FPG levels by approximately 60 to 70 reduce FPG levels by approximately 60 to 70 mg/dL at maximal doses.mg/dL at maximal doses.

• Glycemic-lowering onset is slow, and maximal Glycemic-lowering onset is slow, and maximal glycemic-lowering effects may not be seen glycemic-lowering effects may not be seen until 3 to 4 months of therapy.until 3 to 4 months of therapy.

• The efficacy of both drugs is dependent on The efficacy of both drugs is dependent on sufficient insulinemia. If there is insufficient sufficient insulinemia. If there is insufficient endogenous insulin production (endogenous insulin production (ββ-cell -cell function) or exogenous insulin delivery via function) or exogenous insulin delivery via injections, neither will lower glucose injections, neither will lower glucose concentrations efficiently.concentrations efficiently.

• Patients who are more obese, or who gain Patients who are more obese, or who gain weight on either medication tend to have a weight on either medication tend to have a larger reduction in HbA1c values.larger reduction in HbA1c values.

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EFFICACYEFFICACY• Pioglitazone consistently decreases plasma

triglyceride levels by 10% to 20%, whereas rosiglitazone tends to have a neutral effect. LDL-C concentrations tend to increase with rosiglitazone 5% to 15%, but do not significantly increase with pioglitazone.

• Both appear to convert small, dense LDL particles, which have been shown to be highly atherogenic, to large, fluffy LDL particles, that are less dense. Large, fluffy LDL particles may be less atherogenic.

• Both drugs increase HDL similarly, up to 3 to 9 mg/dL.

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MICRO and MACRO VASCULAR MICRO and MACRO VASCULAR COMPLICATIONSCOMPLICATIONS

• Thiazolidinediones reduce HbA1c Thiazolidinediones reduce HbA1c levels, which have been shown to be levels, which have been shown to be related to the risk of microvascular related to the risk of microvascular complications.complications.

• Macrovascular outcome studies are in Macrovascular outcome studies are in progress. Thiazolidinediones improve progress. Thiazolidinediones improve endothelial function, raise HDL levels, endothelial function, raise HDL levels, slightly lower blood pressure, and have slightly lower blood pressure, and have been shown to reduce restenosis after been shown to reduce restenosis after percutaneous transluminal coronary percutaneous transluminal coronary artery stenting.artery stenting.

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ADVERSE EFFECTS.ADVERSE EFFECTS.

• Troglitazone, the first thiazolidinedione approved, caused hepatotoxicity and had 28 deaths from liver failure, which prompted removal from the U.S. March 2000.

• No evidence of hepatotoxicity was reported in an analysis of more than 5,000 patients given rosiglitazone or pioglitazone.

• Several case reports of hepatotoxicity with rosiglitazone or pioglitazone have been reported, but improvement in ALT was consistently noted when the drug was discontinued.

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HEPATOTOXICITYHEPATOTOXICITY• Prior to therapy, it is recommended that Prior to therapy, it is recommended that

an ALT be checked. ALT monitoring an ALT be checked. ALT monitoring vigilance has been lowered, and it is now vigilance has been lowered, and it is now recommended that the ALT be checked recommended that the ALT be checked periodically at the practitioner’s periodically at the practitioner’s discretion.discretion.

• Prior guidelines recommended every 2 Prior guidelines recommended every 2 months for the first year of therapy, then months for the first year of therapy, then periodically. Patients with ALT levels periodically. Patients with ALT levels >>2.5 times the upper limit of normal 2.5 times the upper limit of normal should not start either medication, and if should not start either medication, and if the ALT is the ALT is >>3 times the upper limit of 3 times the upper limit of normal the medication should be normal the medication should be discontinued.discontinued.

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• Hypersensitivity to GlitazonesHypersensitivity to Glitazones• Type 1 diabetesType 1 diabetes• Presence of clinical liver Presence of clinical liver

abnormalitiesabnormalities• PregnancyPregnancy• CHFCHF

CONTRAINDICATIONCONTRAINDICATION

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SIDE EFFECTSIDE EFFECT

1.1. Fluid retention – edema in 5% of Fluid retention – edema in 5% of case4s ? Mechanismcase4s ? Mechanism

2.2. Aggravation of CHF ( any degree )Aggravation of CHF ( any degree )3.3. In Europe until now combination In Europe until now combination

with insulin is contraindicatedwith insulin is contraindicated4.4. Weight gain, moderate, plateaus Weight gain, moderate, plateaus

over timeover time5.5. Hepatic dysfunction with Hepatic dysfunction with

Troglitazone but not with Troglitazone but not with rosiglitazone, it has significant rosiglitazone, it has significant hepatic toxicity hepatic toxicity

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PREVENTION OF PREVENTION OF NIDDMNIDDM• Aggressive management of cardiovascular Aggressive management of cardiovascular

disease risk factors in type 2 DM is necessary disease risk factors in type 2 DM is necessary to reduce the risk for adverse cardiovascular to reduce the risk for adverse cardiovascular events or death.events or death.

• Smoking cessation, use of anti-platelet Smoking cessation, use of anti-platelet therapy as a primary prevention strategy, therapy as a primary prevention strategy, aggressive management of dyslipidemia aggressive management of dyslipidemia minimally to goal low density lipoprotein-minimally to goal low density lipoprotein-cholesterol (LDL-C) (cholesterol (LDL-C) (<<100 mg/dL) and 100 mg/dL) and secondarily to raise high-density lipoprotein-secondarily to raise high-density lipoprotein-cholesterol (HDL-C) to ≥40 mg/dL, and cholesterol (HDL-C) to ≥40 mg/dL, and treatment of hypertension (again often treatment of hypertension (again often requiring multiple drugs) minimally to requiring multiple drugs) minimally to <<130/80 mm Hg are vital.130/80 mm Hg are vital.

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PREVENTION OF PREVENTION OF NIDDMNIDDM• Prevention stratigies for prevention

of NIDDM are established:– Lifestyle modification– Dietary restriction of fat– Aerobic exercises for 30 minutes 5

times a week, and– Weight loss

• To date, medications have been less effective than lifestyle changes to prevent progression to type 2 DM.

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PATIENT PATIENT EDUCATIONEDUCATION• Patient education and ability to Patient education and ability to

demonstrate self-care and adherence to demonstrate self-care and adherence to therapeutic lifestyle and pharmacologic therapeutic lifestyle and pharmacologic interventions are crucial to successful interventions are crucial to successful outcomes.outcomes.

• Multidisciplinary teams of health care Multidisciplinary teams of health care professionals including physicians professionals including physicians (primary care, endocrinologists, (primary care, endocrinologists, ophthalmologists, and vascular surgeons), ophthalmologists, and vascular surgeons), podiatrists, dietitians, nurses, podiatrists, dietitians, nurses, pharmacists, social workers, behavioral pharmacists, social workers, behavioral health specialists, and certified diabetes health specialists, and certified diabetes educators are needed to optimize these educators are needed to optimize these outcomes in persons with diabetes outcomes in persons with diabetes mellitus.mellitus.

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TEAM APPROACH TO THE TREATMENT TEAM APPROACH TO THE TREATMENT OF THE DIABETIC PATIENTOF THE DIABETIC PATIENT

PhysicianPhysician

Fitness TrainerFitness Trainer

NurseNurseEducatorEducator

DieticianDietician

PharmaciPharmacistst

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Questions?

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THANK THANK YOUYOU