master template

1
Combination Therapy for Type 2 Diabetes
Presented in Dalton, GA on Aug 14, 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
• - 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
Treat to Target Study A1C Decrease
24
Patients in Target (A1C lt 7)
25
Bedtime Glargine vs NPH, With 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
26
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

27
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

28
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

29
Type 2 Diabetes A Progressive Disease

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

30
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 (eg,
  corticosteroids)
• Surgery
• Pregnancy
• Renal or hepatic disease

31
MIMICKING NATURE WITH INSULIN THERAPY

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

6-19
32
Starting Basal Insulin

• Continue oral agent(s) at same dosage
• May later reduce
• Add single insulin glargine dose (Wt x 0.1
  units)
• Usually at bedtime
• Adjust dose to normalize fasting SMBG
• Increase insulin dose q 3 d as needed
• Increase 4 U if FBG gt 140 mg/dL
• Increase 2 U if FBG 110 to 140 mg/dL
• Treat to target (usually lt 110 mg/dL)

33
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

34
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
35
Managing Type 2 Diabetes Four Months or Lessto
Goal 1
36
Managing Type 2 DiabetesGoal 2 (HbA1c lt7.0)
37
(No Transcript)
38
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

39
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

40
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

41
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
42
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
43
ICU Survival

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

Van den Berghe NEJM 20013451359
44
Protocol for Insulin in Hospitalized Patient

• Glucommander While NPO
• hs Wt() x 0.1 Glargine
• Meals Eaten 1.5 units per 15 Gm CHO eaten
• BG gt150 (BG-100) / CF
• CF 7000 / Wt()
• Do Not Use Sliding Scale Only
• Any BG lt80 D50 (100-BG) x 0.3 ml
• Maintain INT
• Do Not Hold Insulin When BG Normal

45
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

46
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
47
Improvement in HbA1c with Increased BG Testing
48
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
49
CARBOHYDRATE TO INSULIN RATIO CIR 2.8 BW /
TDD
Median slope 2.82
Data file IPDC020510A1cCIRs2, 127 pts
50
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
22.8 x Wt / TDD
51
Correction of Hypoglycemia with Glucose100-BG X
0.15 Grams
52
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
53
Correction Factor The 1700 Rule
CF 1724 / TDD n 166
54
Future of Diabetes Management Improvements in
Insulin Delivery

• Insulin analogs and inhaled insulin
• External pumps
• Internal pumps
• Closed-loop systems

55
Conclusion
Intensive therapy to target is the only way to
treat patients with diabetes
1. Metformin Glinide or Sulfonylurea
2. Glargine Glinide or Sulfonylurea
3. Glargine
Lispro/Aspart
4. Insulin Pump