CASE STUDY 3*

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Current Paradigms in the Rx of Type 2 DM
A cost effective, practical approach to glycemic
control
C.R.Kannan, M.D. Consultant in Endocrinology,
Southwest Medical Associates, Las Vegas,
NV Former Chairman of Endocrinology, Cook County
Hospital, Chicago, Illinois Professor of
Medicine, Rush University, Chicago
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Las Vegas Review Journal, Oct 28. 08
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Outline
ADA guidelines for control
ADA/EASD algorithm
Incretin mimetic therapy When and How
Basal Insulin therapy in DM 2
Bolus Insulin therapy in DM 2
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The epidemic of Type 2 Diabetes
20-24 million ..
And Growing!
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!
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4300 Endocrinologists!
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Outline
ADA guidelines for control
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Less than 40 of patients with Diabetes have A1c
lt 7
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Outline
ADA/EASD algorithm
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T2DM Is Characterized by Insulin Deficiency and
Insulin Resistance
Slide 15
Overweight, Inactivity (Inherited/Acquired)
SU
TZD
TZD
Metformin
Insulin
Insulin
Insulin
Insulin
Hyperglycemia
FFA, free fatty acid T2DM, type 2 diabetes
mellitus. Yki-Järvinen H. In Pickup JC, Williams
G, eds. Textbook of Diabetes 1. 3rd ed.
200322.1-22.19.
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6
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TZDs Weight gain Fluid retention Triggering
CHF Osteoporosis Expense CV safety
SU Hypoglycemia Weight gain Secondary
failure Half dose vs full dose
In a recent controversial(2007) meta analysis
involving 42 trials Nissen and Wolski report
that use of Avandia was associated with a 43
increase in MI and a 63 increase in death
compared to placebo or other therapies for DM-2
If A1c gt 7
If A1c gt 7
If A1c gt 7
Intensify Insulin rx
Add TZD
Add Basal Insulin
Add SU
If A1c gt 7
If A1c gt 7
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Basal Insulin
Intensive Insulin MF TZD
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Sulfonylurea or TZD
Basal Insulin (Glargine)
Exenatide (Byetta)
DPP4 Inhibitor Sitagliptin (Januvia)
Diet and Exercise for all choices
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Outline
Incretin mimetic therapy When and How
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Exogenous Glucose
satiety
Suppresses glucose production
Delays gastric absorption
Post prandial benefits
Insulin
Glucagon
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The Incretin System

• Components of the incretin system
• Glucagon-like peptides
• GLP-1

Exenatide Byetta
DPP4 Inhibitors Januvia
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DPP4 inhibitors such as Sitagliptin (Januvia)
inhibit the degradation of Incretins and thus
prolong the half life of endogenous GLP1 (
Glucagon Like Polypeptide 1) and GIP( Glucose
dependent Insulinotropic Peptide
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A simple plan for treatment of DM 2..
Advantage No hypoglycemia Disadvantages -Decline
in A1c modest (07-0.9 -Expense -Adverse effects
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A simple plan for treatment of DM 2..
Triple orals Metformin SU TZD
Metformin Byetta ( SU)
However...
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Exenatide (Byetta)
However..
Addition of Byetta to MF/ SU or both Lowers A1c
by an average of ONLY 0.8-1.5 (occasionally 2)
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Exenatide (Byetta) in patients with DM2 failing
on OHA
Weight Loss!!
Change in A1c
0.5 0 -0.5 -1.0
Change in weight in lbs
0 -2 -4
PBO
PBO
5 bid
10 bid
5 bid
0.1
10 bid
1.4
3.1
4.2
-0.9
-0.6
Side effects NAUSEA, VOMITING PANCREATITIS Inject
ion BID Cost
218 213 216
8.5 8.4 8.5
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Outline
Basal Insulin therapy in DM 2
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Summary At what point of the treatment paradigm
should insulin be brought into play?
Type 2 Diabetic failing on Dual therapy why
do they fail?
A simple plan for treatment of DM 2..
If not at goal in 90 days
It is time for adding basal Insulin!
Metformin SU TZD
Metformin Byetta SU
6
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Type 2 Diabetic failing on Dual therapy why
do they fail?
Build up of Glucotoxicity
Reversible
Eventual beta cell failure
Type 11/2 Diabetes
Irreversible
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TYPE 2 DIABETES . . . A PROGRESSIVE
DISEASE Progressive Decline of ?-Cell Function
in the UKPDS
100
Insulin reserve
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. 1995441249-1258.
6-4
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After 5-10 years of DM-2 Insulin Rx
becomes necessary to attain and maintain
target A1c of less than 7
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Insulin Secretory PatternsBasal vs Mealtime
peaks
Basal Insulin decreases Hepatic Gluconeogenesis
Basal
Mealtime
120
100
80
?U/mL
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Plasma insulin
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Normal
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Basal secretion
0600
1200
1800
2400
0600
Time of Day
Basal Insulin is required 24 hours a day
Riddle. Diabetes Care. 199013676-686.
6-18
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Ideal Insulin Replacement RegimenMimicking
Physiology With Basal and Prandial Insulin1
Breakfast
Lunch
Dinner
Basal Insulin decreases inappropriate hepatic
gluconeogenesis
What does basal insulin do?
Prandial or Bolus
Plasma Insulin
Basal
400 800 1200 1600 2000 2400 2800 3200
Time
1. White JR Jr et al. Postgrad Med.
200311330-36.
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Peak not 24 hours
SC injection0.3 IU/kg
NPH
N20 T1DM patients
0 4 8 12 16 20 24
Time (h)
Comparison of Basal Insulins Pharmacodynamics of
NPH and LANTUS
GIR, glucose infusion rate SC, subcutaneous
NPH, neutral protamine Hagedorn insulin. Please
see Important Safety Information for LANTUS on
slides 31-32. Please see accompanying full
Prescribing Information for LANTUS. LANTUS
Prescribing Information. Sanofi-aventis U.S. LLC
April 2006.
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(insulin glargine rDNA origin injection)1
A-chain
S
S
Gly
Asn 21
Gly 1
Ile 2
Gin 5
Cys 6
Cys 7
Thr 8
Ser 9
Ile 10
Cys 11
Ser 12
Leu 13
Tyr 14
Gin 15
Leu 16
Glu 17
Asn 18
Tyr 19
Cys 20
Val 3
Glu 4
S
S
S
S
Cys 19
Glu 21
Arg 22
Gly 23
Phe 24
Phe 25
Tyr 26
Thr 27
Pro 28
Lys 29
Thr 30
Gly 20
Arg 31
Arg 32
Phe 1
Val 2
His 5
Leu 6
Cys 7
Gly 8
Ser 9
His 10
Leu 11
Val 12
Glu 13
Ala 14
Leu 15
Tyr 16
Leu 17
Val 18
Asn 3
Gin 4
B-chain
Produced by recombinant DNA technology 2
modifications in the amino acid sequence of the
insulin molecule create a stable
molecule. 1. Lantus Prescribing Information,
2005.
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Please see accompanying full Prescribing
Information. Please see Important Safety
Information at the end of the presentation.
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Basal Insulin ComparisonsPharmacodynamics of
glargine (Lantus) and NPH

• LANTUS (insulin glargine rDNA origin
  injection) has a prolonged
• duration of action (24 hours) and a relatively
  constant profile with
• no pronounced peak

SC injection0.3 IU/kg
NPH
N20 T1DM patients
LANTUS
0 4 8 12 16 20 24
Time (h)
Comparison of Basal Insulins Pharmacodynamics of
NPH and LANTUS
GIR, glucose infusion rate SC, subcutaneous
NPH, neutral protamine Hagedorn insulin. Please
see Important Safety Information for LANTUS on
slides 31-32. Please see accompanying full
Prescribing Information for LANTUS. LANTUS
Prescribing Information. Sanofi-aventis U.S. LLC
April 2006.
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Treat-to-Target Trial Study Concept

• Insulin-naïve T2DM patients (N756) mean age, 55
  years BMI, 32 kg/m2diabetes duration, 8-9
  years using 1 or 2 OADs A1C 7.5-10

NPH Insulin Continued OADs
LANTUS Continued OADs
Insulin starting dose 10 units/day titrated
weekly till FASTING GLUCOSE 80-120 end point 24
weeks A1c
Riddle MC et al. Diabetes Care.
2003263080-3086.
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Treat-to-Target Trial Titrated Basal Insulin
Reduced FPG and A1C in Both Treatment Groups

• Adding basal insulin is an effective option for
  patients not adequately controlled using oral
  agents alone

Treat-to-Target Trial Titrated Basal Insulin
Reduced FPG and A1C in Both Treatment Groups
9
200
(insulin glargine rDNA origin injection)
NPH
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Target Goal
Efficacy Safety
Mean FPG (mg/dL)
A1C ()
150
7
6
100
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Time (wk)
Time (wk)
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Treat-to-Target Trial Conclusions

• Structured titration of once-daily bedtime basal
  insulin plus OADs restored A1C to ?7 in
  approximately 57 of patients
• The Treat-to-Target trial offers a simple way to
  initiate basal insulin in patients who are
  overweight, have an A1C of 7.5-10, and are
  taking oral agents
• This simple regimen may facilitate earlier and
  effective insulin use in routine medical
  practice, improving achievement of recommended
  standards of diabetes care

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Lack of adequate basal insulin secretion
Increased hepatic gluconeogenesis
Increased fasting hyperglycemia
Increased PP
Increased Glucotoxicity
Oral agents fail
A1c high
Glucotoxicity
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Decreases hepatic gluconeogenesis
Decreases fasting hyperglycemia
Better PP control
Decreases Glucotoxicity
Oral agents kick in if ß cells are viable
A1c drops
Insulin Rescue
How does one provide basal insulin as a continuum?
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How to start Glargine (Lantus)
Wt in Kg x 0.5 TDD (Total Daily Dose)
50 of this is basal 50 is prandial
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How to start Glargine (Lantus)
80 Kg male x 0.5 40 units TDD (Total Daily
Dose)
Total Daily Dose (Kg x 0.5)
20 units starting dose Plus orals
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How to titrate the dose of Glargine
Weekly Insulin Titration Algorithm
Dosage Initial 20 units titration to FPG ?100
mg/dL without hypoglycemia
LANTUS DoseIncrement (IU/day)
Mean FPG (mg/dL)
2
100-120
4
120-140
6
140-180
8
?180
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Implementing New Titration Strategies With
aBasal Insulin

• An ADA/EASD consensus algorithm for the
  initiation and adjustment of a basal insulin
  regimen is indicated as follows

Start with a long-acting basal insulin, initiated
at 10-20 IU/day
3 2 1
Days u till 100
Check fasting glucose daily and increase dose by
2 IU every 3 days until fasting levels are in
target range (70-130 mg/dL)
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Practical advantages of Basal Insulin Rx with
Glargine
Easy Safe Food Flexible Convenient
1. Easy to start
2. Easy to titrate
3. Only parameter to follow FBG
4. Not tied to meal
5. Negligible risk of hypo- NO PEAK!
6. Only one shot and stay on the pills
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Options for basal insulin
Pre mix insulin
Levemir insulin
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Premixed Insulins

70/30 Novolin
70 NPH and 30 R
70 biphasic Aspart and 30 Aspart
70/30 Novolog Mix
75 Intermediate and 25 Lispro
75/25 Humalog
50 Intermediate 50 Lispro
50/50 Humalog
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Premix Insulins
Disadvantages
Advantages
Convenience of 2 in One Covers meals Works
well when the TDD is less than 40 u
1. BID administration 2. FIXED amounts of both
insulins 3. Cannot change one without
changing the other 4. Not a true basal 5. MUST
EAT for 2 insulins since both have
peaks 6. Titration involves checking 2 BG 7.
Cannot adjust when BG erratic
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A simple plan for treatment of DM 2..
Advancing Insulin.. STEP therapy
Start with basal insulin Glargine and
titrate till Fasting is at goal
If A1c levels are above goal despite fixing the
fasting add step Rx with Bolus (Meal) Insulin
with the largest meal
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Keep Metformin, stop SU
and stop TZD
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Outline
Bolus Insulin therapy in DM 2
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Mechanism of Action Dissociation and Absorption
of Insulin Lispro, and Insulin Aspartand
Glulisine
Peak Time 15-40 minutes
Lispro (Humalog Aspart (Novolog) Glulisine
(Apidra)
CapillaryMembrane
Peak Time 80-120 minutes
RHI
SC, subcutaneous RHI, regular human
insulin. Please see Important Safety Information
for APIDRA on slides 53-55. Please see
accompanying full Prescribing Information for
APIDRA. De Felippis MR et al. In Port D Jr et
al, eds. Ellenberg Rifkins Diabetes Mellitus,
6th ed. 2003.
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If the A1c remains gt7, despite control of
fasting glucose (90-120).. the problem is
post prandial
Pre meal control Basal Insulin Glargine Fix the
Fasting First
Find the meal associated the highest 2 hour PP
Cover that ONE meal with rapid acting STEP
THERAPY
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How to dose prandial Insulin
Based on Lantus dose
Basal Insulin Dose Prandial Insulin dose
1/3Lunch
1/3BF
1/3 Dinner
Start coverage with the largest meal
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STEP APPROACH Advancing basal-bolus
therapy
14 U Rapid Acting Analog with dinner
12 U Rapid Acting Analog
Fixed amount (1/3 of basal insulin glargine
dose)

121-150 add 1 Unit 151-180 add 2 Units
181-210 add 3 Units 211-240 add 4
Units 241-270 add 5 Units
Variable amount based on pre meal BG of 160
2 U rapid acting analog supplemental
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How to dose prandial Insulin
Based on Lantus dose Based on Pre meal BG
Based on Carbs consumed
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How to dose prandial Insulin carb ratio
Calculate the carbohydrate ratio Rule of 500
For aspart or lispro glulisine
500 TDD (Total daily dose)
The resulting number grams of carbs covered by
1 unit
If Total Daily Dose (TDD) is 50 Units
500 50

10 carbs 1 unit meal Insulin
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How to dose prandial Insulin carb ratio
Plan on taking 6 units to cover the meal
If 60 grams of Carbs are planned for dinner
Plus
Supplement the dose based on ..
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How to dose prandial Insulin
Based on Lantus dose Based on Carbs consumed
Correction factor
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Correction Factor ( rule of 1800)
For aspart lispro glulisine
1800 TDD
The resulting number The mg of blood glucose
lowered
by 1 extra unit insulin
example Total Daily Dose (TDD) 60 units
Correction factor 301
Pre meal blood glucose 180 mg
Pre meal goal 120 mg (60 mg higher)
Add 2 units extra to the planned bolus dose
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Five Easy Pieces
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Five Easy Pieces
2. Titrate Basal Insulin to goal 90-120 mg
Use the (2-4-6-8 rule ) or the (1-2-3
method)
Use the half and half rule (1/2 x Wt in KG half
of this is basal)
1. Start basal Insulin Glargine
Monitor PP BG to determine which meal is
the worst and start meal insulin at 1/3 of basal
dose
3. If A1c is above goal start meal insulin
(step rx) (Fixed rate)
5. Titrate Bolus dose based on 2 hr PP goal lt160
4. Add supplemental dose to bolus (Variable
rate)
Use correction factor Rule of 1800 (1800/TDD)
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