master template

1
Combination Therapy for Type 2
Diabetes Springfield, IL, Nov 15, 2003
Paul Davidson, MD, FACE Atlanta Diabetes
Associates Atlanta, Georgia
2
ACE / AACE Targets for Glycemic Control

• HbA1c lt 6.5
• Fasting/preprandial glucose lt 110 mg/dL
• Postprandial glucose lt 140 mg/dL

ACE / AACE Consensus Conference, Washington DC
August 2001
3
Goals of Intensive Diabetes Management
A Normal HbA1c Is Not Everything.
It Is the Only Thing!
4
TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE
Natural History and Treatment
Post-meal glucose
Plasma Glucose
Fasting glucose
126 mg/dL
Insulin resistance
Wt Loss
Exercise
Relative ?-Cell Function
Sensitizes
Secretors
Insulin
Insulin secretion
-10
0
-20
10
20
30
Years of Diabetes
Adapted from International Diabetes Center (IDC).
Minneapolis, Minnesota
5
TYPE 2 DIABETES . . . A PROGRESSIVE
DISEASE Progressive Decline of ?-Cell Function in
the UKPDS
100
80
60
?-Cell Function ( ?)
40
20
0
?10
?9
?8
?7
?6
?5
?4
?3
?2
?1
0
1
2
3
4
5
6
Years
Adapted from UK Prospective Diabetes Study
(UKPDS) Group. Diabetes. 1995 441249-1258.
6-4
6
Basal vs Mealtime Hyperglycemia in Diabetes
Basal hyperglycemia
Mealtime hyperglycemia
250
200
Type 2 Diabetes
150
Plasma Glucose (mg/dL)
100
50
Normal
0
0600
1200
1800
2400
0600
Time of Day
? AUC from normal basal gt1875 mgm/dL.hr Est
HbA1c gt8.7
Riddle. Diabetes Care. 199013676-686.
6-18
7
When Basal Corrected
Basal vs Mealtime Hyperglycemia in Diabetes
Basal hyperglycemia
Mealtime hyperglycemia
250
200
150
Plasma Glucose (mg/dL)
100
50
Normal
0
0600
1200
1800
2400
0600
Time of Day

• ? AUC from normal basal 900 mgm/dL.hr Est HbA1c
  7.2

6-18
8
When Mealtime Hyperglycemia Corrected
Basal vs Mealtime Hyperglycemia in Diabetes
Basal hyperglycemia
Mealtime hyperglycemia
250
200
150
Plasma Glucose (mg/dL)
100
50
Normal
0
0600
1200
1800
2400
0600
Time of Day
? AUC from normal basal 1425 mgm/dL.hr Est HbA1c
7.9
6-18
9
When Both Basal Mealtime Hyperglycemia
Corrected
Basal vs Mealtime Hyperglycemia in Diabetes
Basal hyperglycemia
Mealtime hyperglycemia
250
200
150
Plasma Glucose (mg/dL)
100
50
Normal
0
0600
1200
1800
2400
0600
Time of Day
? AUC from normal basal 225 mgm/dL.hr Est HbA1c
6.4
6-18
10
Step Therapy

• Diet
• Exercise
• Sulfonylurea or Metformin
• Add Alternate Agent
• Add hs NPH
• Switch to Mixed Insulin bid
• Switch to Multiple Dose Insulin

Utilitarian, Common Sense, Recommended
Prone to Failure from Misscheduling and
Mismanagement
11
Stumble Therapy

• YAG Diet
• Golf Cart Exercise
• Sample of the Week Medication
• Interupted,
• Not Combined
• Poor Understanding of Goals
• Poor Monitoring

HbA1c gt8 (If Seen)
Informed Patient Refers Self Elsewhere
12
PETS TherapyStep--Spelled BackwardsAll at once,
nothing first, Just like
bubbles, when they burst.

• Start with Fast to Glucose lt126 mg/dL
• IV Insulin
• Feed PSMF Diet
• Add SU, MF, TZD, Repaglanide prn Lispro for BG
  lt150
• Normal BG from Day 1
• Monitor BG qid
• See Patient Monthly, HFP
• HbA1c Bimonthly

GI Problems Cut MF Hypoglycemia Cut
SU Hypoglycemia Again Cut Repaglinide Allow 2
Month to See TZD Effect
13
Mean Hemoglobin A1CPETS Rx
14
Insulin

• only

most
powerful
powerful
The agent we haveto
control glucose
15
Comparison of Human Insulins / Analogues

• Insulin Onset of Duration ofpreparations
  action Peak action

Regular 3060 min 24 h 610 h
NPH/Lente 12 h 48 h 1020 h
Ultralente 24 h Unpredictable 1620 h
Lispro/aspart 515 min 12 h 46 h
Glargine 12 h Flat 24 h
16
Short-Acting Insulin AnalogsLispro and Aspart
Plasma Insulin Profiles
400
500
Regular Lispro
Regular Aspart
450
350
400
300
350
250
300
Plasma insulin (pmol/L)
200
250
Plasma insulin (pmol/L)
200
150
150
100
100
50
50
0
0
0
30
60
90
120
180
210
150
240
0
50
100
150
200
300
250
Time (min)
Time (min)
Meal SC injection
Meal SC injection
Heinemann, et al. Diabet Med. 199613625629
Mudaliar, et al. Diabetes Care. 19992215011506.
17
Short-Acting Analogs Lispro and Aspart

• Convenient administration immediately prior to
  meals
• Faster onset of action
• Limit postprandial hyperglycemic peaks
• Shorter duration of activity
• Reduce late postprandial hypoglycemia
• Frequent late postprandial hyperglycemia
• Need for basal insulin replacement revealed

18
Limitations of NPH, Lente,and Ultralente

• Do not mimic basal insulin profile
• Variable absorption
• Pronounced peaks
• Less than 24-hour duration of action
• Cause unpredictable hypoglycemia
• Major factor limiting insulin adjustments
• More weight gain

19
Insulin GlargineA New Long-Acting Insulin Analog

• Modifications to human insulin chain
• Substitution of glycine at position A21
• Addition of 2 arginines at position B30
• Gradual release from injection site
• Peakless, long-lasting insulin profile

Gly
Substitution
1
Asp
5
10
15
20
1
5
10
15
20
25
30
Extension
Arg
Arg
20
Glargine vs NPH Insulin in Type 1 DiabetesAction
Profiles by Glucose Clamp
6
NPH
5
Glargine
4
Glucose utilization rate (mg/kg/h)
3
2
1
0
0
10
20
30
Time (h) after SC injection
End of observation period
Lepore, et al. Diabetes. 199948(suppl 1)A97.
21
Glucose Infusion Rate
n 20 T1DM Mean SEM
SC insulin
24 20 16 12 8 4 0
4.0 3.0 2.0 1.0 0
µmol/kg/min
mg/kg/min
CSII
Glargine
0 4 8 12 16 20 24
Time (hours)
Lepore M, et al. Diabetes. 20004921422148.
22
Treat to Target Study NPH vs Glargine in DM2
patients on OHA

• Add 10 units Basal insulin at bedtime
  (NPH or Glargine)
• Continue current oral agents
• Titrate insulin weekly to fasting BG lt 100 mg/dL
• Based on average FBG of 6th and 7th day
• - if 100-120 mg/dL, increase 2 units
• - if 120-140 mg/dL, increase 4 units
• - if 140-160 mg/dL, increase 6 units
• - if 160-180 mg/dL, increase 8 units

23
The Treat-to-Target Trial Randomized addition of
glargine or human NPH insulin to oral therapy of
type 2 diabetic patients Riddle, Rosenstock,
Gerich

DIABETES CARE 2003 263080-2083
24
Percentage of Patients in Target (A1C lt 7)
The Treat-to-Target Trial Randomized addition of
glargine or human NPH insulin to oral therapy of
type 2 diabetic patients Riddle, Rosenstock,
Gerich

DIABETES CARE 2003 263080-2083
25
The Treat-to-Target Trial Randomized addition of
glargine or human NPH insulin to oral therapy of
type 2 diabetic patients Riddle, Rosenstock,
Gerich

DIABETES CARE 2003 263080-2083
26
The Treat-to-Target Trial

. Bedtime Glargine
vs NPHWith Mealtime Regular
48
4
Glargine
NPH
36
3

24
2
Weight (kg)
Patients ()
12
1

0
0
Nocturnal
Weight Gain
Hypoglycemia
P lt .0007P lt .02 (compared to
NPH) Rosenstock, et al. Diabetes. 199948(suppl
1)A100.
6-52
27
The Treat-to-Target Trial Randomized addition of
glargine or human NPH insulin to oral therapy of
type 2 diabetic patients Riddle, Rosenstock,
Gerich

DIABETES CARE 2003 263080-2083
28
Treatment to Target Study NPH vs Glargine in DM2
patients on OHA

• 57 had HbA1c lt7
• Nocturnal Hypoglycemia reduced by 42 in the
  Glargine group
• 33 had HbA1c lt7 without any nighttime
  hypoglycemia in glargine group
• Results significantly better than with NPH

29
Establishing Basal Requirement for Glargine
Body Weight in pounds x 0.1 Give twice in first
day? Average am BG x 2 after five days Add to
Glargine (BG-100)/10 Repeat weekly Example
200 20 units glargine stat and q hs AM BG
averages 200 on 6th and 7th day Add (BG-100)10
to glargine, i.e. increase from 20 to 30 units
q hs 2nd week--average 130 increase glargine
from 30 to 33
30
Overall Summary Glargine

• Insulin glargine has the following clinical
  benefits
• Once-daily dosing because of its prolonged
  duration of action and smooth, peakless
  time-action profile
• Comparable or better glycemic control (FBG)
• Lower risk of nocturnal hypoglycemic events
• Safety profile similar to that of human insulin

31
Goals of Intensive Diabetes Management

• Near-normal glycemia
• HbA1c less than 6.5
• Avoid short-term crisis
• Hypoglycemia
• Hyperglycemia
• DKA
• Minimize long-term complications
• Improve QOL

32
Type 2 Diabetes A Progressive Disease

• Over time, all patients will need insulin to
  control glucose

33
Insulin Therapy in Type 2 Diabetes Indications

• Significant hyperglycemia at presentation
• Hyperglycemia on maximal doses of oral agents
• Decompensation
• Acute injury, stress, infection, myocardial
  ischemia
• Severe hyperglycemia with ketonemia and/or
  ketonuria
• Uncontrolled weight loss
• Use of diabetogenic medications (e.g.
  corticosteroids)
• Surgery
• Pregnancy
• Renal or hepatic disease

34
MIMICKING NATURE WITH INSULIN THERAPY

• All persons need
• both basal and mealtime insulin
• (endogenous or exogenous)
• to control glucose

6-19
35
Advancing to Multiple Dose Insulin

• Indicated when FBG acceptable but
• HbA1c gt 6.5
• Insulin options
• Add mealtime lispro/aspart
• Oral agent options
• Stop sulfonylurea
• Continue metformin for weight control
• Continue glitazone for insulin sensativity

36
Goals in Management of Type 2 Diabetes

• Fasting BG lt126 mg/dl
• Less Than 4 Months
• HbA1c lt7.0
• Less Than 8 Months

i.e. 6
37
Managing Type 2 Diabetes Four Months or Lessto
Goal 1
38
Managing Type 2 DiabetesGoal 2 (HbA1c lt7.0)
39
(No Transcript)
40
GEMS--Glargine Evening
Mealtime Secretagogue

• Basal Dosing
• (Weight in s x 0.1)
• Glargine hs
• Prior to Meals
• Short Acting Secretagogue
• Rapaglinide 2 mg
• Nateglinide 120 mg
• Glimepiride 2 mg

41
Routine Hospital Care for Type 2 Diabetes The
Case for GEMS

• Usually metformin contra-indicated
• Glargine insulin required for normal am glucose
• Stress or steroids
• Interrupted and/or unreliable food intake
• Nursing routine problems
• Lispro insulin at time of tray
• Reluctance to give lispro with normoglycemia
• Supplemental lispro with elevated glucose
• Short-acting secretagogue in half hour before
  tray
• Little risk of hypoglycemia if limited intake

42
Infections in Diabetes

• One BG gt220 mg/dl results in 5.8 times increase
  in nosocomial infection rate
• Two hours hyperglycemia results in impaired WBC
  function for weeks
• Pomposelli, New England Deaconess,
• J Parenteral and Enteral Nutrition
  2277-81,1998

43

Intravenous Insulin with Severe Illness

• Three major recent studies
• DIGAMI Prospective Randomised Study of
  Intensive Insulin Treatment
  on Long
  Term Survival After Acute Myocardial Infarction
  in Patients with Diabetes Mellitus Malmberg, et
  al. BMJ. 19973141512-1515.
• Portland Continuous Insulin Infusion Reduces
  Mortality in Patients with Diabetes Undergoing
  Coronary Artery Bypass Grafting
• Furnary et al J Thorac Cardiovasc Surg
  20031231007-21
• Leuven Intensive Insulin Therapy in Critically
  Ill Patients
• Van den Berghe et al N Engl J Med 2001 345
  1359-67

44
DIGAMI StudyDiabetes, Insulin Glucose Infusion
in Acute Myocardial Infarction(1997)

• Acute MI With BG gt200 mg/dl
• Intensive Insulin Treatment
• IV Insulin For gt24 Hours
• Four Insulin Injections/Day For gt3 Months
• Reduced Risk of Mortality By 28 Over 3.4 Years
• 51 in Those Not Previous Diagnosed

Malmberg BMJ 19973141512
45
Cardiovascular RiskMortality After MI Reduced
by Insulin Therapy in the DIGAMI Study
IV Insulin 48 hours, then
4 injections daily
All Subjects
Low-risk and Not Previously on Insulin
.7
.7
(N 620)
(N 272)
.6
.6
Risk reduction (51)
Risk reduction (28)
.5
.5
P .011
P .0004
.4
.4
.3
.3
.2
.2
.1
.1
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Years of Follow-up
Years of Follow-up
Malmberg, et al. BMJ. 19973141512-1515.
6-11
46
Mortality of DM Patients Undergoing CABG
Fumary et al J Thorac Cardiovasc Surg
20031231007-21
47
Intensive Insulin Therapy in Critically Ill
Patients

• 1548 Patients
• All with BG gt200 mgm/dl
• Randomized into two groups
• Conventional group (BG 180-200)
• Intensive group (BG 80-110)
• Maintained on IV insulin while in ICU
• Goal BG lt110 mg/d
• 1.74 X mortality in conventional group

Van den Berghe NEJM 20013451359
48
ICU Mortality Effect of Average BG Van den Berghe
et al (Crit Care Med 2003 31359-366)
P0.0009
BGgt150
110ltBGlt150
BGlt110
P0.026
49
Protocol for Insulin in Hospitalized Patient

• IV insulin while NPO
• Basal insulin Wt() x 0.1 Glargine hs
• Bolus insulin 1 unit rapid insulin per 10 Gm
  CHO eaten
• Correction bolus for BG gt150 (BG-100) / CF
  units rapid insulin
• CF 7000 / Wt()
• Do Not Use Sliding Scale Only
• Any BG lt80 D50 (100-BG) x 0.3 ml IV
• Do Not Hold Insulin When BG Normal

50
If HbA1c is Not to Goal i.e. 6.5

• SMBG
• frequency
• recording
• memory meter
• Diet
• accurate CHO counting
• appropriate CHO/insulin bolusing

• Infusion site areas
• Overtreatment of low BG
• Delayed or undertreatment of high BG

51
If HbA1c Not to Goal i.e. 6.5

• SMBG
• frequency
• recording
• memory meter

• Infusion site areas
• Overtreatment of low BG
• Delayed or undertreatment of high BG

(100-BG) x 0.2

• Diet
• accurate CHO counting
• appropriate CHO/insulin bolusing

More than 4/day
1700 Rule
2.8 x Wt / TDD
52
Improvement in HbA1c with Increased BG Testing
53
If HbA1c Not to Goal i.e. 6.5

• SMBG
• frequency
• recording
• memory meter

• Infusion site areas
• Overtreatment of low BG
• Delayed or undertreatment of high BG

(100-BG) x 0.2

• Diet
• accurate CHO counting
• appropriate CHO/insulin bolusing

More than 4/day
1700 Rule
2.8 x Wt / TDD
54
CARBOHYDRATE TO INSULIN RATIO CIR 2.8 BW /
TDD
Median slope 2.82
Data file IPDC020510A1cCIRs2, 127 pts
55
If HbA1c Not to Goal i.e. 6.5

• SMBG
• frequency
• recording
• memory meter

• Infusion site areas
• Overtreatment of low BG
• Delayed or undertreatment of high BG

(100-BG) x 0.2

• Diet
• accurate CHO counting
• appropriate CHO/insulin bolusing

More than 4/day
1700 Rule
2.8 x Wt / TDD
56
Correction of Hypoglycemia with Glucose100-BG X
0.15 Grams
57
If HbA1c Not to Goal i.e. 6.5

• SMBG
• frequency
• recording
• memory meter

• Infusion site areas
• Overtreatment of low BG
• Delayed or undertreatment of high BG

(100-BG) x 0.2

• Diet
• accurate CHO counting
• appropriate CHO/insulin bolusing

More than 4/day
1700 Rule
2.8 x Wt / TDD
58
Correction Factor The 1700 Rule
CF 1708 / TDD n 179
59
 
Total

Daily
Wt Wt
CIR Insulin CF

(kg)
(lb) (gm/unit) (unit)
(mg/dL/unit)
149329 47
2088 142313 43
2184 135298 39
2280 129284
35 2376 123270
32 2472 117258
29 2569 111245
26 2665 106234
24 2862 101222
22 2959 96212
20 3057 92202
18 3254 87192
16 3351 83183
15 3549 79174
13 3747 75166
12 3944 72158
11 4142 68151
10 4340 65143 9
4538 62137 8
4736 59130 7
4935 56124 7
5233 54118 6
5531 51112 5
5730 49107 5
6029 46102 5
6327 4497 4
6626 4292 4
7025 4088 3
7323 3884 3
7722 3680 3
8121 3576 3
8520 3372 2
8919 3169 2
9318 3066 2
9818 2863 2
10317 2760 2
10816 2657 1
11315 2554 1
11914 2351 1
12514
Accurate Insulin Management (AIM) Nomogram

• Connect the columns with a straight line between
  weight and total daily dose of insulin (TDD).
• Read correction factor (CF) and
  carbohydrate/insulin ratio (CIR).
• Basal insulin is one-half total daily dose of
  insulin.

60
Future of Diabetes Management Improvements in
Insulin Delivery

• Insulin analogs and inhaled insulin
• Smart external pumps
• Internal pumps
• Real-time sensors
• Closed-loop systems
• Unconceived-of solutions

61
Conclusion
Intensive therapy to target is the only way to
treat patients with diabetes
1. Metformin and/or TZD Glinide or
Sulfonylurea (PETS)
2. Glargine Glinide or Sulfonylurea (GEMS)
3. Glargine Lispro/Aspart (MDI)
4. Insulin Pump (CSII)
62
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