Module 2: Pathophysiology

1
Module 2 Pathophysiology
2
Plasma Insulin After Oral GlucoseEffects of
Obesity and Diabetes
Bagdade, et al. J Clin Invest. 1967461549-1557,
with permission.
2-4
3
Insulin Sensitivity in IGT and DiabetesGlucose
Disposal Rates at Identical Plasma Insulin Levels
200
150
Glucose Disposal Rate(mg/m2/min)
100
50
0
Normal
IGT
Type 2 Diabetes
Kolterman, et al. J Clin Invest. 198168957-969.
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4
Module 4 Practical Approach to Therapy
5
TYPE 2 DIABETESMetabolic Targets

• Parameter Target Value
• Fasting glucose whole blood 80-120
  mg/dLplasma-referenced 90-130 mg/dL
• HbA1coptimal lt6goal lt7action level gt8
• Total cholesterol lt200 mg/dL
• LDL-C optimal lt100 mg/dL initiate
  treatment gt130 mg/dL
• HDL-C gt45 mg/dL
• Triglycerides lt200 mg/dL

Data from American Diabetes Association. Diabetes
Care. 199922 (suppl 1)S32-S41 The National
Cholesterol Education Program (NCEP) Expert
Panel. JAMA. 19932092015-3023.
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Antihyperglycemic Agents for Type 2 DiabetesThe
Six Classes

• Class Available Agents
• a-Glucosidase inhibitor Acarbose, miglitol
• Thiazolidinedione Pioglitazone, rosiglitazone
• Biguanide Metformin
• Meglitinide Repaglinide, nateglinide
• Sulfonylurea Glimepiride, glipizide, glyburide,
  and first-generation sulfonylureas
• Insulin Many

Awaiting FDA approval.
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Antihyperglycemic AgentsMajor Sites of Action
Plasma glucose
?-GlucosidaseInhibitors
Glitazones
Carbohydrate Absorption
Glucose Uptake
()
()
Glucose Production
GI tract
Muscle/Fat
()
Injected Insulin
Metformin
Liver
()
()


Insulin Secretion
Sulfonylureas Meglitinides
Insulin Secretion
Pancreas
()
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The Thiazolidinediones (Glitazones)Basic
Characteristics of Glitazones

• Mechanism of action Enhance muscle and
  adipose tissue response to insulin
• Depends upon Presence of insulin and
  resistance to its action
• Power Decreases HbA1c 0.5 to 1.5
• Dosing Once or twice daily
• Side effects Edema, weight gain, anemia
• Main risk Liver failure (? troglitazone only)

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MONOTHERAPYPioglitazone or RosiglitazoneEffects
on HbA1c
Rosiglitazone
1
1
Pioglitazone
?0.7
?0.7
0
0
0.0
Change of Mean HbA1c ()
Change of Mean HbA1c ()
?0.3
?0.3
?0.3
?0.7
?0.9
?1
?1
Placebo
15 mg QD
30 mg QD
45 mg QD
Placebo
4 mg QD
8 mg QD
4 mg BID
?2
?2
Placebo-adjusted ? at 45 mg ?1.6
Placebo-adjusted ? at 4 mg BID ?1.5
Patel, et al. Diabetes. 199847(suppl 1)A17
Actos (pioglitazone) package insert 7/99.
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The Insulin SecretagoguesBasic Characteristics
of the Sulfonylureas and the Meglitinides
Mechanism of action Increase basal and
postprandial insulin secretion Depends upon
Functioning ?-cells Power Decreases HbA1c 1 to
2 Dosing Once or twice daily (sulfonylureas) th
ree times daily (meglitinides) Side
effects Weight gain Main risk Hypoglycemia
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MANAGEMENT GUIDELINESSelected Insulin
SecretagoguesDosing 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(extended release) Glyburide 1.25
mg, 2.5 mg, 5 mg 1.25 mg-20 mg 5 mg-10 mg
BID Nateglinide 120 mg 120 mg-360 mg 120 mg
TID(not yet available) Repaglinide 0.5 mg, 1 mg,
2 mg 1 mg-16 mg 4 mg TID
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MANAGEMENT GUIDELINESa-Glucosidase Inhibitors,
Biguanides, ThiazolidinedionesDosing
Information
Recommended UsualGeneric Name Dose
Strengths Daily Dose Range Maximal
Effect Acarbose 25 mg, 50 mg, 25-100 mg TID 50 mg
TID 100 mg Miglitol 25 mg, 50 mg, 25-100 mg
TID 50 mg TID 100 mg Metformin 500 mg, 850
mg, 500 mg QD- 1000 mg BID 1000 mg 850 mg
TID Pioglitazone 15 mg, 30 mg, 45 mg 15-45 mg
QD 45 mg QD Rosiglitazone 2 mg, 4 mg, 8 mg 2 mg
QD-8 mg QD 4 mg BID or 4 mg BID
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MANAGEMENT GUIDELINESInsulin Secretagogues
(Sulfonylureas and Meglitinides)
Best candidates Disease duration lt10 years Not
recommended in Renal failure (sulfonylureas) Start
ing dosage Glimepiride 1-2 mg QD Glipizide
(extended release) 2.5-5 mg QD Glyburide
1.25-5 mg QD or BID Nateglinide 120 mg TID
Repaglinide 1 mg TID Adjust
dosage Weekly, if needed Monitoring method SMBG

Awaiting FDA approval.
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MANAGEMENT GUIDELINESPioglitazone and
Rosiglitazone
Best candidates Marked obesity, insulin
resistance Not recommended Contraindicated if
ALT gt2.5 x upper limit of normal. Use with
caution and monitor more often if ALT 1-2.5 x
upper limit of normal Starting
dosage Pioglitazone 30 mg QD Rosiglitazone 4
mg QD Adjust dosage If needed, increase dosage in
4-8 wk Stop if no improvement in 12-16 wk
Monitoring method ALT every 2 mo for 1 yr and
SMBG Stop therapy ALT gt3 x upper limit of normal
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MANAGEMENT GUIDELINESInitial Treatment
Recommendations
FBG gt126 mg/dL
Diet exercise
FBG 126-140 mg/dL
FBG 140-200 mg/dL
200-240 mg/dL
gt240 mg/dL
No symptoms
Symptoms
Sulfonylureas
Metformin
Metformin
Sulfonylureas
Glitazone
Glitazone
Metformin
Sulfonylureas
Insulins
?-Glucosidase Inhibitors
Meglitinides
?-Glucosidase Inhibitors
If FPG gt140 mg/dL or HbA1c gt8
Early combination therapy
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Module 5 Combination Therapy
17
ADA Consensus on Type 2 Diabetes Therapy
Combination TherapyFrequently used or well
studied Sulfonylurea Metformin Sulfonylurea
Rosiglitazone Sulfonylurea Pioglitazone Sulfonyl
urea Acarbose Repaglinide Metformin Rosiglitaz
one Metformin Pioglitazone Metformin Sulfonylu
rea Insulin Metformin Insulin Pioglitazone
Insulin Rosiglitazone Insulin Acarbose
Insulin Infrequently used and/orless well
studied Sulfonylurea Metformin
Glitazone Sulfonylurea Metformin
Insulin Glitazone Metformin Insulin
Nonpharmacologic TherapyDietExercise
Glycemic goals not achieved
Glycemic goals not achieved
Very symptomatic Severe hyperglycemia Ketosis Unre
cognized IDDM Pregnancy
Monotherapy Sulfonylureas Biguanides a-Glucosidase
Inhibitors Glitazones Meglitinides Insulin
Insulin Intermediate BID Intermediate Regular
BID Multiple (3 or more) injections
Glycemic goals not achieved
Modified from American Diabetes Association.
Diabetes Care. 1995181510-1518.
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Combination Therapy in Type 2 DiabetesDecision
Considerations

• HbA1c efficacy
• Reductions from baseline
• Reaching target
• Synergy of mechanisms of action
• Side effects and toxicity profile
• Frequency and severity of hypoglycemia
• Effect on weight gain
• Avoiding polypharmacy and complex regimens
• Compliance and convenience
• Cost

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COMBINATION THERAPYEstimated Improvements in
Glycemic Control
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
agents Open to Target Open to Target
DeFronzo, et al. N Engl J Med. 1995333541-549
Horton, et al. Diabetes Care. 1998211462-1469
Coniff, et al. Diabetes Care. 199518817-824
Moses, et al. Diabetes Care. 199922119-124
Schneider, et al. Diabetes. 199948(suppl
1)A106 Egan, et al. Diabetes. 199948(suppl
1)A117 Fonseca, et al. Diabetes. 199948(suppl
1)A100.
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COMBINATION THERAPYSulfonylurea
GlitazoneEffects on HbA1c
Glyburide Rosiglitazone
Glyburide Pioglitazone
1
1
?0.6
?0.1
0
0
Change of Mean HbA1c ()
Change of Mean HbA1c ()
?0.3
?0.8
?1
?1
P?0.05
?1.2
Gly Placebo
Gly Placebo
4 mg QD
15 mg QD
30 mg QD
?2
?2
Placebo-adjusted ? at 30 mg ?1.3
Placebo-adjusted ? at 4 mg ?0.9
Schneider, et al. Diabetes. 199948(suppl
1)A106 Avandia (rosiglitazone) package insert
4/00.
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COMBINATION THERAPYMetformin
GlitazoneEffects on HbA1c
Metformin Pioglitazone
Metformin Rosiglitazone
1
1
?0.4
?0.2
0
0
Change of Mean HbA1c ()
Change of Mean HbA1c ()
?0.6
?0.6
?0.8
?1
?1
Met Placebo
30 mg QD
Met Placebo
4 mg QD
8 mg QD
?2
?2
Placebo-adjusted ? ?0.8
Placebo-adjusted ? at 8 mg ?1.3
Egan, et al. Diabetes. 199948(suppl 1)A117
Fonseca, et al. JAMA. 20002831695-1702.
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MANAGEMENT GUIDELINESCombinations of Oral
AgentsSulfonylurea-Based Regimens
Start with Long-acting sulfonylurea once
daily (glimepiride or extended-release
glipizide) Add Metformin(preferred
order) or Glitazone (if intolerance or
contraindication for metformin present) or ?-Glu
cosidase inhibitor (if intolerance or
contraindication for both metformin and
glitazone present)
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COMBINATION THERAPYInsulin GlitazoneEffects
on HbA1c
1
1
Insulin Pioglitazone
Insulin Rosiglitazone
?0.1
0
0
Change of Mean HbA1c ()
Change of Mean HbA1c ()
?0.3
?0.6
?1
?1
?1.0
?1.2
?1.3
Ins Placebo
Ins Placebo
15 mg QD
30 mg QD
2 mg BID
4 mg BID
?2
?2
Placebo-adjusted ? at 30 mg ?1.0
Placebo-adjusted ? at 4 mg BID ?1.3
Rubin, et al. Diabetes. 199948(suppl 1)A110
Raskin, et al. Diabetes. 199948(suppl 1)A95.
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COMBINATION THERAPYInsulin Metformin or
GlitazoneEffects on Plasma Glucose
Continuous insulin infusion
Continuous insulin infusion
Continuous insulin infusion plus metformin
Continuous insulin infusion plus glitazone
Glitazone
Metformin
1000
1000
800
800
600
600
Plasma Glucose (mg/dL)
Plasma Glucose (mg/dL)
400
400
200
200
0
0
0800
1200
1600
2400
0800
0800
1200
1600
2400
0800
Time of Day
Time of Day
Troglitazone was the glitazone used in this
study, but is no longer FDA-approved for clinical
use. Yu, et al. Diabetes. 1999482414-2421.
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COMBINATION THERAPYInsulin Metformin or
GlitazoneEffects on Plasma Insulin
Continuous insulin infusion
Continuous insulin infusion
Continuous insulin infusion plus metformin
Continuous insulin infusion plus glitazone
Metformin
Glitazone
1000
1000
800
800
31 insulin dose reduction
53 insulin dose reduction
600
600
Plasma Insulin (pmol/L)
Plasma Insulin (pmol/L)
400
400
200
200
0
0
0800
1200
1600
2400
0800
0800
1200
1600
2400
0800
2000
2000
Time of Day
Time of Day
Troglitazone was the glitazone used in this
study, but is no longer FDA-approved for clinical
use. Yu, et al. Diabetes. 1999482414-2421.
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PRACTICAL GUIDELINESStarting Basal Insulin

• Continue oral agent(s) at same dosage (eventually
  reduce)
• Add single, evening insulin dose (around 10 U)
• NPH (bedtime)
• 70/30 (evening meal)
• Glargine (bedtime or anytime?)
• Adjust dose by fasting SMBG
• Increase insulin dose weekly as needed
• Increase 4 U if FBG gt140 mg/dL
• Increase 2 U if FBG 120 to 140 mg/dL
• Treat to target (usually lt120 mg/dL)

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Practical Management of Type 2 Diabetes Mellitus
FBG gt126 mg/dL
Diet and Exercise
Monotherapy
126-140 mg/dL
140-200 mg/dL
200-240 mg/dL
240-300 mg/dL
gt300 mg/dL
Glitazones Metformin Acarbose
Sx
No Sx
No Sx/Sx
Sx
No Sx
Acarbose
Repaglinide
Insulin
Sulfonylurea
Sulfonylurea
Sulfonylurea
Glitazones
Metformin
Sulfonylurea
Sulfonylurea
Metformin
Oral Combination
Triple Therapy

• Evolving criteria
• If FBG gt140 mg/dL (126 mg/dL?)
• HbA1c gt8 (7?)
• Add second oral agent and titrate to maximum dose

• If no improvement
• Try triple therapy?
• Or continue oral agent(s) insulin Rx at PM or HS

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MANAGEMENT GUIDELINESCombination Therapy in Type
2 DiabetesPragmatic Approach

• Early combination of insulin secretagogue
  insulin sensitizer
• Most simple and cost effective
• Combination of selective sensitizers
• If target HbA1c lt7 not achieved
• Try triple therapy?
• Continue oral agent(s) Insulin Rx at PM or HS
  using Insulin Pen

once-daily Sulfonylurea (AM)
Metformin (PM)
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Insulin Pen
5-21