แนวทางการเลือกใช้ยาเม็ดลดระดับนํ าตาล

Treatment of DiabetesTreatment of Diabetes

•• DDietiet

•• EExercisexercise

•• OOral hypoglycemic agents (OHAs)ral hypoglycemic agents (OHAs)

•• IInsulinnsulin

Indications for OHAsIndications for OHAs

Uncontrolled hyperglycemia or unsatisfactory glycemic control after lifestyle modifications (diet and exercise)

FPG < 130 mg%

HbA1c < 7%

Postprandial PG < 180 mg%

Contraindications to OHAsContraindications to OHAs

1. Decompensated liver disease / renal failure

2. Type 1 diabetes, pancreatic diabetes

3. Stress conditions

4. During Surgery4. During Surgery

5. During Pregnancy

6. Acute diabetic complications

7. Sulfa allergy (sulfonylureas)

8. Poor tissue perfusion (metformin)

Classification of Oral Hypoglycemic Agents

•• Insulin secretagoguesInsulin secretagogues

1. Sulfonylurea1. Sulfonylurea2. Non2. Non--sulfonylureasulfonylurea

•• Insulin sensitizersInsulin sensitizers•• Insulin sensitizersInsulin sensitizers1. Biguanide1. Biguanide2. Thiazolidinediones2. Thiazolidinediones

•• Glucosidase inhibitorsGlucosidase inhibitors

Oral hypoglycemic agents for Type Oral hypoglycemic agents for Type 2 2 Diabetes:Diabetes:

Class Available Agents

Sulfonylureas Glipizide, glibenclamide, gliclazide,

gliquidone, glimepiride, and

chlorpropamide

Meglitinides Repaglinide

Biguanides Metformin

Thiazolidinediones Pioglitazone, rosiglitazone

a-Glucosidase inhibitors Acarbose, Voglibose

Pathophysiology of Diabetes

Peripheral TissuesPeripheral Tissues(Muscle and Fat)(Muscle and Fat)

GlucoseLiverLiver InsulinInsulin

resistanceresistance

Small intestineSmall intestine

(carbohydrates)(carbohydrates)

__ +

Impaired or no insulin secretionImpaired or no insulin secretionIncreased or normal glucagon secretionIncreased or normal glucagon secretion

Increased glucose Increased glucose productionproduction

Receptor andReceptor andpostreceptor defectspostreceptor defects

PancreasPancreas

insulin

__ +

Classification of SulfonylureasClassification of Sulfonylureas

• By Generation of Drugs

• First generation- Chlorpropamide, Tolbutamide- Chlorpropamide, Tolbutamide

• Second generation- Glibenclamide, Glipizide

- Gliquidone, Gliclazide

- Glimepiride

Classification of SulfonylureasClassification of Sulfonylureas

• By Duration of Action

• Long Acting:- Chlorpropamide, Glibenclamide- Chlorpropamide, Glibenclamide

• Short Acting:- Tolbutamide, Glipizide

- Gliclazide, Gliquidone

Selected Insulin Secretagogues:Selected Insulin Secretagogues:Dosing InformationDosing Information

Recommended Usual Generic Name Dose Strengths Daily Dose Range Maximal Effect

Glimepiride 1 mg, 2 mg, 4 mg 1 mg-8 mg 4 mg QD

Glipizide 2.5 mg, 5 mg, 10 mg 2.5 mg-20 mg 5 mg-10 mg QD

Glibenclamide 1.25 mg, 2.5 mg, 5 mg 1.25 mg-20 mg 5 mg-10 mg BIDGlibenclamide 1.25 mg, 2.5 mg, 5 mg 1.25 mg-20 mg 5 mg-10 mg BID

Gliclazide 80 mg, 30 mg (MR) 80-400 mg 160-320 mg BID

Nateglinide 120 mg 120 mg-360 mg 120 mg TID

Repaglinide 0.5 mg, 1 mg, 2 mg 1 mg-16 mg 4 mg TID

Insulin Secretagogues (Sulfonylureas and Insulin Secretagogues (Sulfonylureas and Meglitinides)Meglitinides)

Best candidates Disease duration

How to Select SulfonylureasHow to Select Sulfonylureas

• Second Generation, esp. short-acting,

i.e. glipizide, gliclazide, gliquidone

• Glipizide, glibenclamide and• Glipizide, glibenclamide and

glimepiride exert equipotent glucose-

lowering properties

Non Sulfonylurea Insulin SecretagogueNon Sulfonylurea Insulin Secretagogue(Meglitinides)(Meglitinides)

• Repaglinide

• (Nateglinide)• (Nateglinide)

Non Sulfonylurea Insulin SecretagogueNon Sulfonylurea Insulin Secretagogue

• Binds to specific sites on the sulfonylurea

receptor

• Induces a rapid postprandial insulin response• Induces a rapid postprandial insulin response

• Less risk of hypoglycemia is a meal is

missed

Non Sulfonylurea Insulin SecretagogueNon Sulfonylurea Insulin Secretagogue

Clinical Indications:

• Allergic to sulfonylurea

• Elderly with high risk of

hypoglycemia

Comparison: Sulfonylurea VS Comparison: Sulfonylurea VS MegMeglilititinidenide

Sulfonylurea Meglitinide

•Onset/duration

•Potency

slower/longer

HbA1c 1-2.5%

faster/shorter

HbA1c 0.5-1.5%•Potency

•Hypoglycemia

•Renal disease

HbA1c 1-2.5%

more common

avoid/contraindicated

HbA1c 0.5-1.5%

less common

may be usable

The Biguanides (metformin):The Biguanides (metformin):

Mechanism of action Inhibits hepatic glucose production

Power Decreases HbA1c 1% to 2%

Dosing Once, twice, three times daily

Side effects Gastrointestinal symptomsSide effects Gastrointestinal symptoms

Weight loss

Contraindications Renal failure (Cr >2.0), CHF

Best candidate Obese type 2 DM

Main risk Lactic acidosis (in renal failure)

Actions of BiguanideActions of Biguanide

•• Inhibits hepatic gluconeogenesisInhibits hepatic gluconeogenesis

•• Facilitates tissue glucose uptakeFacilitates tissue glucose uptake•• Facilitates tissue glucose uptakeFacilitates tissue glucose uptake

•• Enhances insulin sensitivityEnhances insulin sensitivity

•• No direct effect on beta cellsNo direct effect on beta cells

Biguanide:Biguanide: Side EffectsSide Effects

•• Lactic acidosis*Lactic acidosis*

•• Nausea, vomitingNausea, vomiting•• Nausea, vomitingNausea, vomiting

•• DiarrheaDiarrhea

* risk increased with poor tissue perfusion, renal impairment, and acute stress

Contraindications and guidelines forContraindications and guidelines forwithdrawing metforminwithdrawing metformin

1.1. renal impairmentrenal impairment

2.2. Withdraw during periods of tissue hypoxia (MI, Withdraw during periods of tissue hypoxia (MI,

sepsis)sepsis)sepsis)sepsis)

3.3. Withdraw Withdraw 2 2 days before and days before and 3 3 days after contrast days after contrast

mediummedium--containing iodine, and restart after renal containing iodine, and restart after renal

function has been checkedfunction has been checked

4.4. Withdraw Withdraw 2 2 days before general anesthesia and days before general anesthesia and

restart when renal function is stablerestart when renal function is stable

Thiazolidinedione: Mode of ActionThiazolidinedione: Mode of Action

Inzucchi, 1999

Action of ThiazolidinedioneAction of Thiazolidinedione

•• Insulin sensitivityInsulin sensitivity

•• muscle glucose utilizationmuscle glucose utilization•• muscle glucose utilizationmuscle glucose utilization

•• gluconeogenesisgluconeogenesis

Thiazolidinedione:Thiazolidinedione: Side EffectsSide Effects

•• 22--55 Kg. Weight gainKg. Weight gain

•• Anemia (hemodilution)Anemia (hemodilution)

•• Hepatocellular injuryHepatocellular injury•• Hepatocellular injuryHepatocellular injury

•• Check LFT before useCheck LFT before use

•• Monitor LFT qMonitor LFT q 22 months formonths for 11 yearyear

Comparison: Metformin VS Glitazone (TZDs)Comparison: Metformin VS Glitazone (TZDs)

Metformin TZDs

•Site of action

•Potency

•Weight gain

liver (muscle)

HbA1c 1-1.2%

none (little)

muscle (liver)

HbA1c 1.5-2%

more•Weight gain

•Liver disease

•Kidney disease

•Lipid profile

none (little)

contraindicated

contraindicated

mostly unchanged

more

contraindicated

may be usable

LDL and HDL up

LDL/HDL unchanged

Glucosidase inhibitorsGlucosidase inhibitors

•• Acarbose and VogliboseAcarbose and Voglibose

•• Inhibit enzymes in the small intestine brush Inhibit enzymes in the small intestine brush border to break down oligosaccharides and border to break down oligosaccharides and disaccharides to monosaccharidesdisaccharides to monosaccharidesdisaccharides to monosaccharidesdisaccharides to monosaccharides

•• Shift the absorption to more distal part of small Shift the absorption to more distal part of small intestine and colonintestine and colon

•• Delay glucose entry into the systemic Delay glucose entry into the systemic circulationcirculation

•• GI side effectsGI side effects

INTRALUMINAL INTRALUMINAL BRUSH BORDER BRUSH BORDER CELL TRANSPORTCELL TRANSPORT

MaltoseMaltose

AlphaAlpha--amylaseamylase

Maltose MaltotrioseMaltose Maltotriose

MaltaseMaltase

MaltaseMaltase

GGLLUUCC

Active TransportActive Transport

a Dextrin a Dextrin a Dextrinasea Dextrinase

CCOOSSEE

GlucoseGlucose

FructoseFructose

SucraseSucraseSucroseSucroseActive TransportActive Transport

Passive TransportPassive TransportAcarboseAcarbose

VogliboseVoglibose

TYPE TYPE 2 2 DIABETES IS A PROGRESSIVE DISEASEDIABETES IS A PROGRESSIVE DISEASE

HbA1c Values (7.0% vs 7.9%)

9

8

ADA actionsuggested

Conventional

Intensive

7.4%

8.4%

7.5%

8.7%

8.1%

Med

ian

Hb

A1c

(%)

Progressive Decline of Progressive Decline of --Cell Function in the UKPDSCell Function in the UKPDS

60

80

100

Cel

l Fu

nct

ion

(%

)

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

7

66.2% upper limit of normal range

ADA target

0

0 3 6 9

Years From Randomization

12 18

6.6%

Med

ian

Hb

A

0

20

40

60

10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6

Years-

Cel

l Fu

nct

ion

(%

Combination OralCombination OralHypoglycemic AgentsHypoglycemic AgentsTherapyTherapyTherapyTherapy

Regimen HbA1c FBG

Sulfonylurea + metformin ~1.7% ~65 mg/dL

Sulfonylurea + rosiglitazone ~1.4% ~60 mg/dL

Sulfonylurea + pioglitazone ~1.2% ~50 mg/dL

Estimated Improvements in Glycemic Estimated Improvements in Glycemic ControlControl

DeFronzo, et al. N Engl J Med. 1995;333:541-549; Horton, et al. Diabetes Care. 1998;21:1462-1469; Coniff, et al. Diabetes Care. 1995;18:817-824; Moses, et al. Diabetes Care. 1999;22:119-124; Schneider, et al. Diabetes. 1999;48(suppl 1):A106; Egan, et al. Diabetes. 1999;48(suppl 1):A117; Fonseca, et al. Diabetes. 1999:48(suppl 1):A100.

Sulfonylurea + acarbose ~1.3% ~40 mg/dL

Repaglinide + metformin ~1.4% ~40 mg/dL

Pioglitazone + metformin ~0.7% ~40 mg/dL

Rosiglitazone + metformin ~0.8% ~50 mg/dL

Insulin + oral agents Open to Target Open to Target

Choice of OHAs depends onChoice of OHAs depends on

1. Degree of hyperglycemia

2. Obesity

3. Co-morbidities

4. Glycemic control

5. Tolerability

Treatment Algorithm for OHAs in Type 2 Diabetes

FPG < 250 mg/dlAsymptomatic

FPG < 250 mg/dlSymptomatic

FPG 250-350 mg/dlSymptomatic

FPG > 350 mg/dlSymptomatic

Controlled ?Sulfonylurea

(short acting)Sulfonylurea

(short acting)Metformin

(If FPG < 150, may useMetformin

(If FPG < 150, may use

Diet and exercise(1-2 months)

Diet and exercise(1-2 months)

Contraindication to OHASevere complicationsOral agent failure

Contraindication to OHASevere complicationsOral agent failure

Yes

Controlled ?

No

(short acting)(short acting)(If FPG < 150, may use

glucosidase inhibitor)(If FPG < 150, may use

glucosidase inhibitor)

Combination oral agentsCombination oral agents Insulin (alone or with OHA)Insulin (alone or with OHA)

IF FPG >140 mg/dl, HbA1c>8%, Post prandial PG > 180 mg/dlIF FPG >140 mg/dl, HbA1c>8%, Post prandial PG > 180 mg/dl

Choice of OHAs depends onChoice of OHAs depends on

1. Degree of hyperglycemia

2. Obesity

3. Co-morbidities

4. Glycemic control

5. Tolerability

Metformin in Overweight PatientsCompared with conventional policy

• 32% risk reduction in any diabetes-related endpoints p=0.0023

• 42% risk reduction in diabetes-related deaths p=0.017• 42% risk reduction in diabetes-related deaths p=0.017

• 36% risk reduction in all cause mortality p=0.011

• 39% risk reduction in myocardial infarction p=0.01

UKPDS METFORMIN SUBSTUDY

Intensive Treatment and Weight ChangeM

ean

Ch

ange

(kg

)

Conventional (200)Insulin (199)Chlorpropamide (129)Glibenclamide (148)Metformin (181)5

10

Mea

n C

han

ge (

kg)

0 2 4–5

0

6 8 10Time From Randomization (y)

Baseline = 85 kg

Choice of OHAs depends onChoice of OHAs depends on

1. Degree of hyperglycemia

2. Obesity

3. Co-morbidities

4. Glycemic control

5. Tolerability

Features predicting OHA FailureFeatures predicting OHA Failure

1. Age < 40 years

2. Thin

3. Diabetes > 5 years

4. History of or currently on > 40 units /day

of insulin

Causes of secondary drug failureCauses of secondary drug failure

•• Non compliance: diet, medicationNon compliance: diet, medication

•• Drug interactionDrug interaction

•• Associated stressAssociated stress•• Associated stressAssociated stress

•• Associated diseases:Associated diseases:

-- Cushing’s, Acromegaly, etc.Cushing’s, Acromegaly, etc.

Glycemic Control for Diabetes

Biochemical index Nondiabetic Diabetic goal

suggested*

Preprandial glucose

Type Type 2 2 DiabetesDiabetesFasting BG Fasting BG >> 126 126 mg/dLmg/dLCasual BGCasual BG >> 200 200 mg/dL mg/dL

Systematic Approach to Management of Type 2 Diabetes

HyperglycemiaHyperglycemia Lipid DisordersLipid Disorders HypertensionHypertension ComplicationsComplicationsOther ComponentsOther Components

of Careof Care

Hemoglobin AHemoglobin A11ccEvery Every 33--6 6 monthsmonthsTarget Target 40 40 mg/dlmg/dl

LDL CholesterolLDL CholesterolAnnual testingAnnual testing

Target LDL < Target LDL < 100 100 mg/dlmg/dlWith CVD < With CVD < 100 100 mg/dlmg/dl

Triglycerides Triglycerides < < 200 200 mg/dlmg/dl

HDLHDL> > 40 40 mg/dlmg/dl

Blood PressureBlood Pressure(every visit)(every visit)

Dx of HTN > Dx of HTN > 130130//8585Rx Target < Rx Target < 130130//8080

Blood PressureBlood Pressure(every visit)(every visit)

Dx of HTN > Dx of HTN > 130130//8585Rx Target < Rx Target < 130130//8080

Annual ScreeningAnnual ScreeningNephropathyNephropathy

Microalbuminuria ScreeningMicroalbuminuria Screening

RetinopathyRetinopathyDilated retinal examDilated retinal exam

NeuropathyNeuropathyComprehensive foot examComprehensive foot exam

Annual ScreeningAnnual ScreeningNephropathyNephropathy

Microalbuminuria ScreeningMicroalbuminuria Screening

RetinopathyRetinopathyDilated retinal examDilated retinal exam

NeuropathyNeuropathyComprehensive foot examComprehensive foot exam

Foot CareFoot CareAspirin UseAspirin Use

Tobacco cessationTobacco cessationFlu Shot + Pneumovax Flu Shot + Pneumovax Psychosocial SupportPsychosocial SupportQOL QOL -- Pt. satisfactionPt. satisfaction

Foot CareFoot CareAspirin UseAspirin Use

Tobacco cessationTobacco cessationFlu Shot + Pneumovax Flu Shot + Pneumovax Psychosocial SupportPsychosocial SupportQOL QOL -- Pt. satisfactionPt. satisfaction

Glycemic ControlGlycemic ControlGlycemic ControlGlycemic ControlManagement ofManagement of

DyslipidemiaDyslipidemiaManagement ofManagement of

DyslipidemiaDyslipidemiaHypertensionHypertensionManagementManagementHypertensionHypertensionManagementManagement

ComplicationsComplicationsManagementManagement

ComplicationsComplicationsManagementManagement

CareCareRecommendationsRecommendations

CareCareRecommendationsRecommendations

HyperglycemiaHyperglycemia Lipid DisordersLipid Disorders HypertensionHypertension ComplicationsComplications of Careof Care

แนวทางการเลือกใช้ยาเม็ดลดระดับน้ำตาล

Treatment of Diabetes

Diet

Exercise

Oral hypoglycemic agents (OHAs)

Insulin

Indications for OHAs

Uncontrolled hyperglycemia or unsatisfactory glycemic control after lifestyle modifications (diet and exercise)

FPG < 130 mg%

HbA1c < 7%

Postprandial PG< 180 mg%

Contraindications to OHAs

1. Decompensated liver disease / renal failure

2. Type 1 diabetes, pancreatic diabetes

3. Stress conditions

4. During Surgery

5. During Pregnancy

6. Acute diabetic complications

7. Sulfa allergy (sulfonylureas)

8. Poor tissue perfusion (metformin)

Classification of Oral Hypoglycemic Agents

Insulin secretagogues

1. Sulfonylurea

2. Non-sulfonylurea

Insulin sensitizers

1. Biguanide

2. Thiazolidinediones

Glucosidase inhibitors

Oral hypoglycemic agents for Type 2 Diabetes:

ClassAvailable Agents

Sulfonylureas Glipizide, glibenclamide, gliclazide, gliquidone, glimepiride, and chlorpropamide

MeglitinidesRepaglinide

BiguanidesMetformin

ThiazolidinedionesPioglitazone, rosiglitazone

a-Glucosidase inhibitorsAcarbose, Voglibose

Slide 4-4

Antihyperglycemic Agents for Type 2 Diabetes:

The Six Classes

Six classes of pharmacotherapeutic agents are employed in the treatment of type 2 diabetes mellitus; these include insulin and five classes of orally active agents. Among the oral agents, the sulfonylureas and the biguanides are generally preferred for initial therapy. Two newer sulfonylureas, glimepiride and extended-release glipizide, allow once-daily dosing. In recent years, new oral agents have become available. These include acarbose and miglitol

(a-glucosidase inhibitors), pioglitazone and rosiglitazone (thiazolidinediones), and repaglinide (a meglitinide). The availability of these agents provides additional options for selected patient populations. However, the expansion of the therapeutic menu has made therapeutic decision making more complex.

Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.

Pathophysiology of Diabetes

Peripheral Tissues

(Muscle and Fat)

Glucose

Liver

Impaired or no insulin secretion

Increased or normal glucagon secretion

Increased glucose production

Receptor and

postreceptor defects

Insulin

resistance

Pancreas

Small intestine

(carbohydrates)

insulin

__

+

Classification of Sulfonylureas

By Generation of Drugs

First generation

- Chlorpropamide, Tolbutamide

Second generation

- Glibenclamide, Glipizide

- Gliquidone, Gliclazide

- Glimepiride

Classification of Sulfonylureas

By Duration of Action

Long Acting:

- Chlorpropamide, Glibenclamide

Short Acting:

- Tolbutamide, Glipizide

- Gliclazide, Gliquidone

Selected Insulin Secretagogues:

Dosing Information

RecommendedUsual

Generic NameDose StrengthsDaily Dose RangeMaximal Effect

Glimepiride1 mg, 2 mg, 4 mg1 mg-8 mg4 mg QD

Glipizide2.5 mg, 5 mg, 10 mg2.5 mg-20 mg5 mg-10 mg QD

Glibenclamide1.25 mg, 2.5 mg, 5 mg1.25 mg-20 mg5 mg-10 mg BID

Gliclazide80 mg, 30 mg (MR)80-400 mg160-320 mg BID

Nateglinide120 mg120 mg-360 mg120 mg TID

Repaglinide0.5 mg, 1 mg, 2 mg1 mg-16 mg4 mg TID

Slide 4-25

MANAGEMENT GUIDELINES

Selected Insulin Secretagogues:

Dosing Information

The insulin secretagogues include the sulfonylureas and repaglinide. The sulfonylureas, which are often used as first-line therapy in type 2 diabetes, may be given once or twice daily. The glyburide formulations are given twice daily, and glimepiride or extended-release glipizide is given once daily. Repaglinide must be given three times daily (before meals).

Insulin Secretagogues (Sulfonylureas and Meglitinides)

Best candidatesDisease duration 2.0), CHF

Best candidateObese type 2 DM

Main riskLactic acidosis (in renal failure)

Slide 4-18

The Insulin Secretagogues:

Basic Characteristics of the Sulfonylureas and the Meglitinides

The insulin secretagogues, which include the sulfonylureas and the meglitinides, lower plasma glucose by augmenting insulin secretion by the pancreatic b-cells. These agents are thus effective only if functioning pancreatic b-cells are present. During treatment with the insulin secretagogues, a reduction of glycosylated hemoglobin (HbA1c) by approximately 1.0% to 2.0% may be expected. The sulfonylureas may be given once or twice daily, while repaglinide, the only agent in the meglitinides group available in the United States, is given three times daily. Weight gain is the most notable side effect; allergy occurs rarely. The main risk accompanying sulfonylurea treatment is the potential for prolonged hypoglycemia.

Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.

Actions of Biguanide

Inhibits hepatic gluconeogenesis

Facilitates tissue glucose uptake

Enhances insulin sensitivity

No direct effect on beta cells

Biguanide: Side Effects

Lactic acidosis*

Nausea, vomiting

Diarrhea

* risk increased with poor tissue perfusion, renal impairment, and acute stress

Contraindications and guidelines for withdrawing metformin

renal impairment

Withdraw during periods of tissue hypoxia (MI, sepsis)

Withdraw 2 days before and 3 days after contrast medium-containing iodine, and restart after renal function has been checked

Withdraw 2 days before general anesthesia and restart when renal function is stable

Thiazolidinedione: Mode of Action

Inzucchi, 1999

This cartoon of a thiazolidinedione-sensitive cell demonstrates the end result olf a thiazolidinedione binding to its nuclear PPAR-g receptor. The insulin signal in the nucleus has been augmented resulting in increased number of GLUT-4 tranpsorters and therefore more glucose entry into the cell per unit of time.

1786.ps

Action of Thiazolidinedione

Insulin sensitivity

muscle glucose utilization

gluconeogenesis

Thiazolidinedione: Side Effects

2-5 Kg. Weight gain

Anemia (hemodilution)

Hepatocellular injury

Check LFT before use

Monitor LFT q 2 months for 1 year

Comparison: Metformin VS Glitazone (TZDs)

Metformin TZDs

Site of action

Potency

Weight gain

Liver disease

Kidney disease

Lipid profile

liver (muscle)

HbA1c 1-1.2%

none (little)

contraindicated

contraindicated

mostly unchanged

muscle (liver)

HbA1c 1.5-2%

more

contraindicated

may be usable

LDL and HDL up

LDL/HDL unchanged

Glucosidase inhibitors

Acarbose and Voglibose

Inhibit enzymes in the small intestine brush border to break down oligosaccharides and disaccharides to monosaccharides

Shift the absorption to more distal part of small intestine and colon

Delay glucose entry into the systemic circulation

GI side effects

INTRALUMINAL BRUSH BORDER CELL TRANSPORT

Maltose

Alpha-amylase

Maltose Maltotriose

a Dextrin

Maltase

Maltase

a Dextrinase

GLUCOSE

Glucose

Fructose

Sucrase

Sucrose

Active Transport

Active Transport

Passive Transport

Acarbose

Voglibose

TYPE 2 DIABETES IS A PROGRESSIVE DISEASE

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

9

8

7

6

6.2% upper limit of normal range

ADA target

ADA action

suggested

0

0

3

6

9

Years From Randomization

12

18

Conventional

Intensive

7.4%

6.6%

8.4%

7.5%

8.7%

8.1%

Median HbA1c (%)

HbA1c Values (7.0% vs 7.9%)

0

20

40

60

80

100

10

9

8

7

6

5

4

3

2

1

0

1

2

3

4

5

6

Years

-Cell Function (% )

Progressive Decline of -Cell Function in the UKPDS

Slide 6-3

TYPE 2 DIABETES…A PROGRESSIVE DISEASE

HbA1c in the UKPDS

Major advances in pharmacotherapy in the field of diabetes have given researchers the opportunity to examine the outcomes of treatment strategies over time. The United Kingdom Prospective Diabetes Study (UKPDS) was the largest study of newly diagnosed type 2 diabetes patients ever undertaken. The study included more than 5000 patients who were randomized to receive conventional therapy, various sulfonylurea agents, metformin, or intensive treatment with insulin for about 10 years. The ultimate goals of the management of patients with type 2 diabetes are the same as those in type 1 diabetes: preventing acute and chronic complications associated with diabetes. The current trend is toward aggressive glycemic control early in the diabetic process. In the UKPDS, the relationship between glycemia and the outcome of the study is complex. Even though the difference in glycosylated hemoglobin (HbA1c ) between the conventional treatment group and the intensive treatment group was about the same throughout the study, HbA1c progressively increased regardless of treatment.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.

Combination Oral Hypoglycemic Agents

Therapy

Estimated Improvements in Glycemic Control

DeFronzo, et al. N Engl J Med. 1995;333:541-549; Horton, et al. Diabetes Care. 1998;21:1462-1469; Coniff, et al. Diabetes Care.

1995;18:817-824; Moses, et al. Diabetes Care. 1999;22:119-124; Schneider, et al. Diabetes. 1999;48(suppl 1):A106; Egan, et al. Diabetes. 1999;48(suppl 1):A117; Fonseca, et al. Diabetes. 1999:48(suppl 1):A100.

Regimen HbA1c FBG

Sulfonylurea + metformin~1.7%~65 mg/dL

Sulfonylurea + rosiglitazone~1.4%~60 mg/dL

Sulfonylurea + pioglitazone~1.2%~50 mg/dL

Sulfonylurea + acarbose~1.3%~40 mg/dL

Repaglinide + metformin~1.4%~40 mg/dL

Pioglitazone + metformin~0.7%~40 mg/dL

Rosiglitazone + metformin~0.8%~50 mg/dL

Insulin + oral agentsOpen to Target Open to Target

Slide 5-1b

COMBINATION THERAPY

Estimated Improvements in Glycemic Control

This slide shows summary data on the effectiveness of combination oral diabetes therapy. Although the therapeutic effect in terms of decline of glucose or HbA1c from baseline values or compared with placebo varies considerably from study to study and combination to combination, the most effective combinations appear to be a sulfonylurea in combination with either metformin or a glitazone. The effectiveness of combinations of oral agents permits successful control longer than is possible with monotherapy and delays the need for insulin. With the variety of agents currently available, individualized combination oral therapy can effectively manage patients over a long span in the natural history of type 2 diabetes.

DeFronzo, et al. N Engl J Med. 1995;333:541-549; Horton, et al. Diabetes Care. 1998;21:1462-1469; Coniff, et al. Diabetes Care. 1995;18:817-824; Moses, et al. Diabetes Care. 1999;22:119-124.

Choice of OHAs depends on

1. Degree of hyperglycemia

2. Obesity

3. Co-morbidities

4. Glycemic control

5. Tolerability

Treatment Algorithm for OHAs in Type 2 Diabetes

FPG < 250 mg/dl

Asymptomatic

FPG < 250 mg/dl

Symptomatic

FPG 250-350 mg/dl

Symptomatic

FPG > 350 mg/dl

Symptomatic

Yes

Controlled ?

No

Sulfonylurea

(short acting)

Metformin

(If FPG < 150, may use

glucosidase inhibitor)

Diet and exercise

(1-2 months)

Combination oral agents

Contraindication to OHA

Severe complications

Oral agent failure

Insulin (alone or with OHA)

IF FPG >140 mg/dl, HbA1c>8%, Post prandial PG > 180 mg/dl

Choice of OHAs depends on

1. Degree of hyperglycemia

2. Obesity

3. Co-morbidities

4. Glycemic control

5. Tolerability

Metformin in Overweight Patients

Compared with conventional policy

32% risk reduction in any diabetes-related endpoints p=0.0023

42% risk reduction in diabetes-related deaths p=0.017

36% risk reduction in all cause mortality p=0.011

39% risk reduction in myocardial infarction p=0.01

UKPDS METFORMIN SUBSTUDY

Intensive Treatment and Weight Change

Mean Change (kg)

Conventional (200)

Insulin (199)

Chlorpropamide (129)

Glibenclamide (148)

Metformin (181)

0

2

4

–

5

0

5

10

6

8

10

Time From Randomization (y)

Baseline = 85 kg

Slide 17

UKPDS METFORMIN SUBSTUDY

Intensive Treatments and Weight Change

During 10 years of treatment, the change in body weight was similar in the metformin and conventional policy groups and was lower than that observed

in the sulfonylurea or insulin intensive treatment groups.

UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.

Choice of OHAs depends on

1. Degree of hyperglycemia

2. Obesity

3. Co-morbidities

4. Glycemic control

5. Tolerability

Features predicting OHA Failure

1. Age < 40 years

2. Thin

3. Diabetes > 5 years

4. History of or currently on > 40 units /day

of insulin

Causes of secondary drug failure

Non compliance: diet, medication

Drug interaction

Associated stress

Associated diseases:

- Cushing’s, Acromegaly, etc.

Glycemic Control for Diabetes

Biochemical index Nondiabetic Diabetic goal

suggested*

Preprandial glucose