Type 2 Diabetes Management Goals

1
Type 2 DiabetesManagement Goals

• Prevent and retard microvascular complications
• Early detection and monitoring
• Optimal glycemic control
• Normal blood pressure
• Reduce macrovascular complications
• LDL-Cholesterol lt100 mg/dL (Statins)
• BP lt130/85 mm Hg (ACE inhibitors)
• Weight loss 5 to 10 body weight
• ASA
• No Smoking
• Realistic exercise

2
Implementing Diabetes Treatment GoalsStrategies

• Earlier diagnosis and treatment
• Acting on results of SMBG and HbA1c
• Matching pharmacology and physiology
• Combination therapy
• Multiple oral agents (Type 2)
• Oral agents insulin or insulin analogues (Type
  2)
• Insulin or insulin analogues (Type 1)

3
UKPDSType 2 Diabetes . . . A Progressive
DiseaseEffect of Treatment on HbA1c
Cross-sectional median values (7.0 vs. 7.9)
8.7
9
Conventional Intensive
8.4
8.1
8
7.5
ADA actionsuggested
7.4
Median HbA1c ()
7
ADA target
6.6
6.2 upper limit of normal range
6
0
0
3
6
9
12
15
Years From Randomization
Adapted from UK Prospective Diabetes Study
(UKPDS) Group. Lancet. 1998352837-853.
4
UKPDS THE BOTTOM LINEMain Messages for
Management of Type 2 Diabetes

• Sulfonylureas insulin and metformin are
  effective in reducing risk of complications by
  improving glycemic control
• No evidence of increased risk of complications
  for any single therapy
• Combination therapy required almost from the
  outset to achieve near-normoglycemia
• Much earlier use of insulin Rx in most patients
  as expected therapy in the progressive management
  of Type 2 diabetes

5
How Much Combination Therapy in Type 2 Diabetes
6
Pharmacologic Management of Type 2 Diabetes
Current and Potential Agents

• Insulin Secretagogues
• Sulfonylureas
• Glimepiride
• Glipizide
• Glyburide
• Benzoic acid
• Repaglinide
• D-Phenylalanine
• Nateglinide
• GLP-1
• Delayed Glucose Absorption
• a-Glucosidase Inhibitors
• Acarbose
• Miglitol
• Voglibose

• Insulin Sensitizers
• Metformin
• Glitazones
• Troglitazone
• Rosiglitazone
• Pioglitazone
• Others
• G-1216570
• MCC-555
• PNU-182716
• . . . and INSULIN

7
ADA Consensus on Type 2 Diabetes Therapy
Combination TherapyFrequently used or well
studied Sulfonylurea Metformin Sulfonylurea
Troglitazone Sulfonylurea Pioglitazone Sulfonylu
rea Acarbose Repaglinide Metformin Rosiglitazo
ne Metformin Pioglitazone Metformin Sulfonylur
ea Insulin Metformin Insulin Pioglitazone
Insulin Troglitazone Insulin Acarbose
Insulin Infrequently used and/orless well
studied Sulfonylurea Metformin
Troglitazone Sulfonylurea Metformin
Insulin Troglitazone 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 Zimmerman et al. Diabetes Care.
1995.
8
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

9
Combination Therapy in Type 2 DiabetesEstimated
Improvement
10
Type 2 DiabetesTreat to Target

• HbA1c lt7
• FBG 80-120 mg/dL (4.4 to 6.7 mmol/L)
• Postprandial BG lt180 mg/dL (10 mmol/L)

11
Practical Management of Type 2 Diabetes Mellitus
FBG gt126
All get 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 a different sensitizer
• Or try triple therapy
• Or Continue oral agent(s)and add insulin Rx at
  PM or HS

12
MONOTHERAPYPlacebo-Subtracted Dose-Response to
Oral Agents Effect on HbA1c
0.5
0.5
Glimepiride
Acarbose
0.0
0.0
-0.5
-0.5

0.44
HbA1c ()
HbA1c ()
-1.0
-1.0

0.74

0.77
-1.5
-1.5

1.2
-2.0
-2.0

1.8

1.9
-2.5
-2.5
8 mg
4 mg
1 mg
300 mg
150 mg
75 mg
0.5
Metformin
0.5
Troglitazone
0.0
0.0
-0.5
-0.5

0.4
HbA1c ()
HbA1c ()
-1.0
-1.0

0.7

0.9

1.1
-1.5
-1.5

1.2

1.6

1.7
-2.0
-2.0

2.0
-2.5
-2.5
2500 mg
2000 mg
1500 mg
1000 mg
500 mg
600 mg
400 mg
200 mg
Daily Dose
Daily Dose
Data from Garber et al. Am J Med.
1997103491-497 Goldberg et al. Diabetes Care.
199619849-856 Precose (acarbose tablets).
Bayer Corporation. 1996 Fonseca et al. J Clin
Endocrinol Metab. 1998833169-76.
13
MONOTHERAPYRosiglitazone Effects on HbA1c
Compared to Baseline
Compared to Placebo(Treatment Effect)
1.5
0.9
1.0
0.5
0.0
Change in Mean HbA1c ()
-0.5
-0.3
-1.0
-0.6
-1.5
-1.2
-2.0
-1.5
Placebo
4 mg
8 mg
4 mg
8 mg
Plt0.0001 Plt0.0045 Patel et al. Diabetes.
199847(Suppl 1)A17.
14
MONOTHERAPYPioglitazone Effects on HbA1c
Previously Diet-Only Patients (Naive)
n Baseline HbA1c D from Baseline D from
Placebo Placebo 25 9.0 0.6 15
mg 26 9.9 -0.8 -1.4 30 mg 26 9.3 -0.6 -1.2
45 mg 21 9.9 -1.9 -2.5 Previously
Treated Patients n Baseline HbA1c D from
Baseline D from Placebo Placebo 54 10.9
0.8 15 mg 53 10.4 -0.1 -0.9 30
mg 59 10.4 -0.0 -0.8 45 mg 55 10.6 -0.6
-1.4
P0.05 vs. baseline Schneider et al. Diabetes.
199948 (Suppl 1)A109.
15
Monotherapy in Type 2 Diabetes MellitusSecondary
Failure

• Secondary failure rate 5 to 10 a year(UKPDS 7
  a year)
• Decreasing b-cell function
• Obesity
• Non-adherence to treatment
• Lack of exercise
• Intercurrent illness

16
COMBINATION THERAPYEstimated Improvements in
Glycemic Control
Regimen HbA1c
FBG Sulfonylurea metformin 1.7 65
mg/dL Sulfonylurea troglitazone 0.9-1.8 50-6
0 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 1999 48 (Suppl 1)
A106 Egan et al. Diabetes 1999 48 (Suppl
1)A117. Fonseca et al. Diabetes 199948 (Suppl
1)A100.
17
COMBINATION THERAPYSulfonylurea
MetforminEffect on HbA1c
Glyburide
Metformin
1
Metformin Glyburide
0.2
0
-0.4

• Change in Mean HbA1c ()

-1
-1.7


-2




-3
0
9
13
17
21
25
29
Treatment (wk)
Plt0.01 Plt0.001 vs. glyburide
monotherapy DeFronzo et al. N Engl J Med.
1995333541-49.
18
COMBINATION THERAPYSulfonylurea
TroglitazoneEffect on HbA1c
2.5
Glyburide (G12)
2.0
1.5
T200
1.0
T400
0.9
T600
0.5

• Change in Mean HbA1c ()

T200 G12
0.0
T400 G12
-0.5
-0.9
T600 G12
-1.0
-1.5
-1.8
-2.0
-2.5
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Treatment (wk)
Horton et al. Diabetes Care. 1998211462-69.
19
COMBINATION THERAPYSulfonylurea
PioglitazoneEffect on HbA1c and FBG
10
1.5
0
1.0
5.6
-10
0.5
0.1
-20
0
HbA1c () D from Baseline
FBG (mg/dL) D from Baseline
-30
-0.5
-40
-1.0
-34
-0.8
-50
-1.2
-1.5
-60
-2.0
-52
PSU
PIO 15SU
PIO 30SU
PSU
PIO 15SU
PIO 30SU
P0.05 vs. baseline (paired t-test). P
Placebo PIO 15 Pioglitazone 15 mg PIO 30
Pioglitazone 30 mg SU Sulfonylurea. Schneider
et al. Diabetes 199948 (Suppl 1)A106.
20
COMBINATION THERAPYMetformin GlitazoneEffect
on HbA1c
Metformin Pioglitazone(16 weeks)
Metformin Rosiglitazone(26 weeks)
0.6
0.6
0.4
0.2
0.3
0.3
0
0
HbA1c () D from Baseline
-0.3
-0.3
HbA1c () D from Baseline
-0.6
-0.6
-0.6
-0.6
-0.9
-0.9
-0.8
-1.2
-1.2
PMet
PIO 30Met
PMet
RSG 4 mg qd Met
RSG 8 mg qd Met
P0.05 vs. baseline (paired t-test) P0.05
vs. PMET (Dunnetts test). P Placebo MET
Metformin PIO 30 Pioglitazone 30 mg. Egan et
al. Diabetes 199948 (Suppl 1)A117.
Plt0.0001 Fonseca et al. Diabetes 199948
(Suppl 1)A100.
21
COMBINATION THERAPYMetformin AcarboseEffect
on HbA1c
0.2
Metformin
Metformin Acarbose
0
-0.2
P0.0001

• Mean Change in HbA1c ()

-0.4
-0.6
-0.6
-0.8
0
4
8
12
18
24
End point
Treatment (wk)
Rosenstock et al. Diabetes Care. 1998212050-5.
22
COMBINATION THERAPYSulfonylurea and Metformin
TroglitazoneThe Bottom Line

• Baseline HbA1c 9.7
• HbA1c reduction from baseline -1.3
• Reached target HbA1c lt8 43
• Reached target HbA1c lt7 14
• Estimated cost 10/day

Yale et al. Diabetes 199948 (Suppl 1)A118.
23
MANAGEMENT GUIDELINESCombinations of Oral
AgentsSulfonylurea-Based Regimens

• Start with Long-acting sulfonylurea (Glimepiride
  or extended-release glipizide)
• Add Metformin or Glitazone (If intolerance
  or contraindication for metformin present)

24
MANAGEMENT GUIDELINESSecondary Failure of Oral
Combination Therapy

• Signs FPG gt140 mg/dL (gt120 mg/dL) HbA1c gt8
  (gt7)
• Causes (same as those for monotherapy) Decreas
  ing -cell function Nonadherence to
  treatment Obesity Insufficient
  exercise Intercurrent illness
• Rate Predictable in most patients

25
MANAGEMENT GUIDELINESCombination Therapy in Type
2 DiabetesPragmatic Approach

• Avoid polypharmacy
• Combination of insulin secretagogue insulin
  sensitizer
• Most simple and cost effective
• Combination of selective sensitizers
• If target FBG/HbA1c not achieved
• Try a different sensitizer or try triple therapy
• Continue oral agent(s) Insulin Rx at PM or HS
  using Insulin PenorIntensive insulin Rx alone

once daily Sulfonylurea (AM)
Metformin (PM)
26
MANAGEMENT GUIDELINESOral Agents Insulin in
Type 2 DiabetesRationale

• Simplifies insulin regimen
• Improves glycemic control
• Better patient acceptance
• Compliance
• Convenience
• Lower doses of exogenous insulin
• Less weight gain

27
COMBINATION THERAPY RATIONALEOral Agents
Insulin in Type 2 Diabetes
Synergistic or Complementary Effects

• Sulfonylureas
• Increase hepatic levels of endogenous insulin and
  meet meal-related insulin requirements
• Metformin
• Improves insulin sensitivity at the liver and
  reduces hepatic glucose production
• Glitazones
• Improve insulin action in peripheral tissues and
  enhance glucose uptake
• a-Glucosidase Inhibitors
• Decrease postprandial glucose absorption

28
From Insulin . . . Add-on Pills!
29
COMBINATION THERAPYInsulin TroglitazoneEffect
on HbA1c
Insulin placebo
Insulin troglitazone 200 mg
10.2
Insulin troglitazone 600 mg
9.8
9.4
-0.1
9.0

• Mean HbA1c ()

P lt0.001
8.8
-0.8
8.2
-1.4
7.8
7.4
-8
-6
-4
-2
0
1
2
4
8
10
12
16
20
24
28
Insulin
Combination Therapy
Treatment (wk)
Schwartz et al. N Engl J Med. 1998338861-6.
30
COMBINATION THERAPYInsulin Troglitazone
Effect on HbA1c and Insulin Dose
Placebo Troglitazone 200 mg 600
mg N 118 116 116 HbA1c baseline 9.4 9.5 9.3
Change from baseline -0.1 -0.8 -1.4 Insulin
dosage () change -11 -29
Plt0.0001
Schwartz et al. N Engl J Med 1998338961-6.
31
COMBINATION THERAPYInsulin Rosiglitazone
Effect on HbA1c and Insulin Dose
INSRSG INSRSG INSP 2 mg bid 4 mg
bid N 103 106 103 HbA1c baseline 8.9 9.1 9.0
Change from baseline 0.1 -0.6 -1.2 Insu
lin dosage () change -1 -6 -12
P0.006 vs. INSP Plt0.04 vs. INSRSG 4mg
bd. P Placebo INS Insulin RSG
Rosiglitazone.
Raskin et al. Diabetes 199948 (Suppl 1)A94.
32
COMBINATION THERAPYInsulin Pioglitazone
Effect on HbA1c
1.0
0.5
(9.7)
(9.7)
(9.8)
-0
-0.5
HbA1c ()D from Baseline
-0.3
-1.0
-1.0
-1.5
-1.3
-2.0
-2.5
P INS
PIO 15 INS
PIO 30 INS
Plt0.05 P Placebo PIO 15 Pioglitazone 15 mg
PIO 30 Pioglitazone 30 mg INS
Insulin. Rubin et al. Diabetes 199948 (Suppl
1)A110.
33
COMBINATION THERAPYInsulin MetforminEffect on
HbA1c
8.6
Insulin metformin
8.4
Insulin placebo
8.2
8.0
7.8
7.6

• HbA1c ()

7.4
7.2
7.0
6.8
Intensive MDI
6.6
0
2
6
Combination Therapy
Insulin
Treatment (mo)
Bergenstal et al. Diabetes 199847(suppl 1)A89.
34
From Pills . . . Add-on Insulin!
35
COMBINATION THERAPYGlimepiride InsulinEffect
on FPG and Insulin Dosage
Placebo insulin
Glimepiride insulin titrated to FPG lt140 mg/dL
Insulin Dosage
300
FPG
100





250
75

• Mean mg/dL

200
Mean Units/Day
50

150
25
100
0
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Treatment (wk)
Treatment (wk)
Plt0.001
Plt0.001
Plt0.05
Riddle et al. Diabetes Care. 1998211052-7.
36
COMBINATION THERAPYGlimepiride InsulinEffect
on HbA1c and Insulin Dose

• Placebo Insulin Glimepiride Insulin
• Initial mean HbA1c 9.9 9.7
• Final mean HbA1c 7.7 7.6
• Final insulin dose 78 U/day 49 U/day (-38)
• Subjects needinginsulin dosegt 100 U/day 9/62
  (14) 4/70 (6)
• Dropouts 11/73 (15) 2/72 (3)

Plt0.001 Plt0.01 between-group difference
Data from Riddle et al. Diabetes Care.
1998211052-7.
37
COMBINATION THERAPYSulfonylurea Lispro AC or
NPH at HS or MetforminEffects on HbA1c and Weight
Baseline HbA1c Followup HbA1c Followup Weight
12
12
10.4
10.2
10.0
10
10
-1.9
-1.9
-2.3
8
8
Weight Gain (kg)
HbA1c ()
6
6
4
4
2
2
3.4 kg
0.9 kg
2.3 kg
0
0
Su Metformin (n40)
Su NPH (n50)
Su LP (n42)
Browdoe et al. Diabetes 199948 (Suppl 1)A104.
38
COMBINATION THERAPYThe FINFAT Study
NPH Insulin BID (n24) NPH Insulin HS Glyburide
(n22) NPH Insulin HS Metformin (n19) NPH
Insulin HS Metformin Glyburide (n23)
6
10
4
9
D Body Weight (kg)
HbA1c ()
2
8
0
7
-2
40
0
30
-1
D HbA1c ()
HS Insulin Dose (U)
20
-2
10
-3
0
3
6
9
12
0
3
6
9
12
Time (mo)
Time (mo)
Yki-Jarvinen et al. Ann Intern Med
1999130380-96.
39
COMBINATION THERAPY The FINFAT StudyNPH Insulin
at HS Various Agents
D A1c ()
Dropouts ()
(5/24) 21
0
25
20
-1
(2/24) 8
15
(1/24) 4
NPH at HS
10
(0/24) 0
-2
1.9
2.0
Glyburide Metformin Gly Met NPH at AM
5
2.1
2.5
0
-3
D Weight (Kg)
Insulin Dose
4.6
53
5
60
3.9
3.6
4
36
40
3
24
20
2
0.9
20
1
0
0
Yki-Jarvinen et al. Ann Intern Med
1999130380-96.
40
COMBINATION THERAPYOral Agents Inhaled Insulin
ACEffect on HbA1c
10
9
8
HbA1c ()
7
6
5
Weeks
Plt0.0001 Weiss SR Barger S Cheng S et al.
Diabetes 199948 (Suppl 1)A12.
41
MANAGEMENT GUIDELINESAdding Insulin to an Oral
Agent

• Continue oral agent(s) at same dosage (eventually
  reduce)
• Add single evening insulin dose (10 U) using
  Insulin Pen
• NPH insulin (bedtime)
• 70/30 insulin (evening meal)
• Glargine insulin (basal insulin awaiting
  approval)
• Adjust dose by SMBG (fasting)
• Increase insulin dose weekly if needed
• Increase 4 U if FBG gt180 mg/dL
• Increase 2 U if FBG gt140 mg/dL

Medical Management of Type 2 Diabetes. 4th ed.
Alexandria Va American Diabetes Association
19981-139.
42
Which Insulin is Better and Easier for
Combination Therapy
43
Comparison of Human Insulins
Onset of Duration of Insulin Preparations
Action Peak Action Lispro 5 to 15 min 1 to 2
hr 4 to 6 hr Human Regular 30 to 60 min 2 to 4
hr 6 to 10 hr Human NPH 1 to 2 hr 4 to 6 hr 10 to
16 hr Human Lente 1 to 2 hr 4 to 6 hr 10 to 16
hr Human Ultralente 2 to 4 hr Unpredictable lt24 hr
The time course of action of any insulin may
vary in different individuals or at different
times in the same individual. Because of
thisvariation time periods indicated here
should be considered as general guidelines only.
44
INSULIN TACTICS Twice Daily SplitMixed Regimens
Regular
Lispro
Lispro
Lispro
Insulin Effect
Insulin Effect
Reg
Reg
NPH
NPH
NPH
NPH
B
L
S
HS
B
B
L
S
HS
B
Meals
Meals
45
INSULIN TACTICSMDI NPH Regular AC


NPH at AM and HS Regular AC
NPH at HS Regular AC
Reg
Reg
Insulin Effect
Reg
Reg
Reg
Insulin Effect
NPH
NPH
NPH
B
L
S
HS
B
B
L
S
HS
B
Meals
Meals
46
INSULIN TACTICSMDI NPH Lispro AC


NPH at AM and HS Lispro AC
NPH at HS Lispro AC
Lispro
Lispro
Lispro
Lispro
Lispro
Insulin Effect
Insulin Effect
NPH
NPH
NPH
B
L
S
HS
B
B
L
S
HS
B
Meals
Meals
47
INSULIN TACTICSMDI Ultralente at PM Regular AC
48
INSULIN TACTICS Human Ultralente Insulin A True
Basal Insulin

• N 5 subjects with type 1 diabetes
• Onset of action 2 to 4 hours
• Broad variable peak between 6 and 12 hrs after
  injection

This pattern and the duration of action of
Human Ultralente appear to more closely mimic
those after injection of animal NPH or Lente than
Beef Ultralente.
Freeman SL OBrian PC Rizza RA Diab Res Clin
Pract 12187 1991
49
INSULIN TACTICSMDI The Quest for a Basal Insulin
Combinations of Lispro/NPH AC and NPH at HS
Lalli et al. Diabetes Care. 199922468-477.
50
INSULIN TACTICS The Ideal Basal Insulin

• Mimics normal pancreatic basal insulin secretion
• Long-lasting effect
• Smooth peakless profile
• Reproducible and predictable effects
• Reduced nocturnal hypoglycemia
• Once-daily administration for convenience
• Pharmacodynamic effects similar to insulin pump

51
INSULIN TACTICSInsulin GlargineA New
Long-acting Insulin Analogue

• Modifications to human insulin chain
• Substitution of glycine at position A21
• Addition of two arginines at position B30
• Gradual release pattern from injection site

52
INSULIN TACTICSGlargine Vs. NPH Insulin in Type
1 DMAction Profiles by Glucose Clamp
6
Glargine insulin NPH insulin
5
4
3
Glucose Utilization Rate (mg/kg/h)
2
1
0
0
30
20
10
End of observation period
Time (h) after S.C. Injection
Lepore et al. Diabetes 199948 (Suppl 1)A97.
53
INSULIN TACTICS Glargine vs. NPH Insulin in
Nondiabetic SubjectsPharmacokinetics by Glucose
Clamp
Linkeschowa R et al. Diabetes.199948(Suppl
1)A97.
54
INSULIN TACTICS The Basal/Bolus Insulin Concept

• Basal Insulin
• Insulin requirement to suppress hepatic glucose
  production between meals
• Bolus Insulin (prandial)
• Insulin requirement to maintain normal glucose
  disposal after eating
• Ideally each component should come from
  a different insulin with a specific
  profile
• CSII best model of the Basal/Bolus concept

55
INSULIN TACTICS Insulin Glargine in Type 2
Diabetes

• Baseline HbA1c 8.5
• Similar HbA1c improvement ( 0.4 to 0.6) with
  less nocturnal hypoglycemia and less weight gain
  in the insulin Glargine group

Wt. Gain Nocturnal Hypos NPH 3.1
lb 40 Glargine 0.9 lb 31
Plt0.01 P lt0.02
Rosenstock et al. Diabetes 48(Suppl 1)A100 1999
56
The Potential Role of Basal Insulin
57
INSULIN TACTICS THE FUTUREMDI Glargine at HS
Inhaled Insulin AC
Inhaled Inhaled Inhaled Insulin
Insulin Insulin
Glargine
Insulin Effect
(HOE-901)
B
L
S
HS
B
Meals
58
Combination Oral Agents InsulinStarting
Insulin . . .
59
Evening NPH or Ultralente or 70/30 or Glargine
60
Bridge Therapy