Insulin Therapy For Type 2 Diabetes Mellitus: Akhmad Nurdani

Insulin Therapy for
Type 2 Diabetes Mellitus
Akhmad Nurdani
Department of Internal Medicine

Dr. Soetomo General Hospital- Airlangga University School of Medicine
Surabaya
Type 2 Diabetes: Double Impairment
Impaired ß cell function:
•  insulin secretion
Impaired insulin action:
•  insulin resistance
• Results in unacceptable blood

glucose control
www.diabetesclinic.ca
http://www.who.int/diabetes/actionnow/en/mapdiabprev.pdf
List of countries with the highest numbers of
estimated cases of diabetes for 2000 and 2030
Wild S, et al. Diabetes Care 27:1047–1053, 2004
RISKESDAS, 2007 : Prevalence DM 5,7%

www.cme.medscape.com/viewarticle/587183
UKPDS: Islet -cell function and the
progressive nature of diabetes
100 Time of diagnosis
(% of normal by HOMA)
80
Islet -cell function
60
Pancreatic function
40
= 50% of normal
20
0
10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6
Years
HOMA = homeostasis model assessment
Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25;

UKPDS. Diabetes. 1995;44:1249-1258
Islet β-cell function (HOMA %β)
in the UKPDS
Islet β-cell function (%) Conventional Sulfonylurea
(primarily diet) Metformin
100
Non-overweight Overweight
80
60
40
20 Loss ~4 % per year
0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Years from randomization
UKPDS Study Group. Diabetes. 1995;44:1249-1258

Insulin Therapy
• Traditionally :
• the final “step” of insulin therapy being
administered 10–15 years after diagnosis
• Both patients and physicians are often reluctant

to start insulin because of fears of painful
injections, hypoglycemia,and weight gain
• Insulin Therapy : The “Last Resort”
Inadequate therapy
Change
Paradigm
“Treat to Succeed”
“Treat to fail”
Physiologic Glucose Homeostasis and Insulin
Breakfast Lunch Supper

75
Insulin
Insulin 50
(µU/mL)
25
0 Basal insulin
9.0
Glucose
6.0
Glucose
(mmo/L) 3.0
Basal glucose
0
7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
a.m. p.m.
Time of Day
cme.medscape.com/viewarticle/412864_2
www.cme.medscape.com/viewarticle/412864_2
Glucose is the primary stimulator of insulin secretion
IR signaling pathways.
Le Roith D , Zick Y Dia Care 2001;24:588-597

Copyright © 2011 American Diabetes Association, Inc.
Pharmacokinetics of Insulin
(Novorapid, Humalog, Apidra)
(Humulin R, Actrapid)
(Humulin N, Insulatard)
(Lantus,
Levemir)
Figures of Approximate Pharmacokinetic Profiles of Human Insulin

and Insulin Analogues.
The relative duration of action of the various forms of insulin is shown.

The duration will vary widely both between and within persons.
Insulin Pharmacodynamics
Insulin Analog vs Regular Insulin
Unwanted
hyperglycemia periode
Unwanted
hypoglycemia periode
Treat-to-Target: addition of detemir or
NPH to oral therapy
475 People with Type 2 Diabetes on 1 or 2 Oral Agents
Glycaemic Control Hypoglycaemia (events pt-yr-1)

Baseline HbA1c 8.5% 8.6%
0.0 12
-0.5
 HbA1c
8
-1.0
NPH
-1.5 4
detemir
-2.0 -1.8%
-1.9%
P=NS 0
Final HbA1c 6.6% 6.8% 5.0 6.0 7.0 8.0 9.0
NPH insulin HbA1c (%)
Insulin detemir
Hermansen K et al. Diabetes Care. 2006;29:1269-1274
Addition of glargine or biphasic
aspart to oral therapy
233 People with Type 2 Diabetes on 1 or 2 Oral Agents
Glycaemic Control Hypoglycaemia
Baseline HbA1c 9.7% 9.8% 4 P<0.05
0.0 3.4
Events/Patient-year
-0.5
(PG  3.1 mmol/l)

3
 HbA1c
-1.0
-1.5 2
-2.0
1 0.7
-2.5 -2.4%
-3.0 -2.8%
0
P<0.01
Final HbA1c 6.9% 7.4%
Biphasic aspart 70/30 Glargine

Raskin P et al. Diabetes Care. 2005;28:260-265
Addition of Biphasic, Prandial, or Basal
Insulin to Oral Therapy in Type 2 Diabetes
Mean (±SE) Percentage Change from Baseline to 1 Year in Glycated Hemoglobin, Fasting Plasma
Glucose, Postprandial Glucose, and Body Weight (Panel A) and Mean (+SD) Hypoglycemic-Event
Rate (Panel B)
4-T Study Group, N Engl J Med 2007;357:1716-30
Basal-bolus insulin treatment: matching
insulin administration to insulin needs
Rapid-acting insulins
100
B L D Basal insulins
80
μU/ml
60
40
Normal pattern
20
0600 0800 1200 1800 2400 0600
Time of day
B = breakfast; L = lunch; D = dinner

Riddle MC. CADRE Core Slide Kit. 2003
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239
Glycaemic targets, ADA 2012
More stringent HbA1c targets (e.g. 6.0–6.5% [42–48 mmol/mol]) :

-short disease duration,
-long life expectancy,
-no significant CVD.
if this can be achieved without significant hypoglycaemia or other
adverse effects of treatment
Less stringent HbA1c goals :7.5–8.0% (58–64 mmol/mol) :
-a history of severe hypoglycaemia,
-limited life expectancy,
-Advanced macro and mico vasculer complications,
-Extensive comorbid conditions
-Long standing DM Whom the general goal is difficult to attain
Starting Insulin Therapy
Position Statement of the American Diabetes Association (ADA) and
the European Association for the Study of Diabetes (EASD) 2012
Inzucchi, diabetes care, 2012
What are the problems associated with
insulin therapy?
• Weight gain
• Hypoglycaemia will occur in some people – education is
needed
• Failure of dose titration to get adequate glucose control
• These risks can be minimized by

– use of insulin analogues in those with problems
– using basal insulin only when starting at lower HbA1c
– appropriate education on eating and physical activity
– active and continuing support for dose titration
– intensification of insulin regimens over following years
UKPDS: prevalence of
hypoglycaemia in Type 2 diabetes
Annual percentage of patients reporting ≥1 hypoglycaemic event*
6 5.5%
5
Patients (%)
4 3.8%
2
1.2%
1
0.1% 0.3%
0
Diet Sulfonylurea Metformin Basal Basal +
insulin prandial
insulin
*Hypoglycaemia: temporary incapacity or requiring medical help

Wright AD et al. J Diabetes Complications. 2006;20:395-401
Summary
• Glycemic targets and glucose-lowering therapies must

be individualized.
• Diet, exercise, and education remain the foundation of
any type 2 diabetes treatment program
• Ultimately, many patients will require insulin therapy
alone or in combination with other agents to maintain
glucose control.
• Insulin effectively lowers HbA1c, thereby reducing the
risks of both micro- and macrovascular complications
• All insulins : weight gain and risk hypoglycemia.
• The larger the doses and the more aggressive the
titration, the lower the HbA1c,  greater likelihood
of adverse effects.
• Generally long-acting insulin analogs reduce the
incidence of overnight hypoglycemia, and rapid-
acting insulin analogs reduce postprandial glucose
excursions as compared with corresponding human
insulins (NPH, Regular), but they generally do not
result in clinically significantly lower HbA1c.
The Ominous Octet
Islet -cell
Decreased
Incretin Effect
Increased
Impaired Lipolysis
Insulin Secretion
Islet a-cell
Increased Increased Glucose

Glucagon Secretion Reabsorption
Increased
Decreased Glucose
HGP
Neurotransmitter Uptake
DeFronzo Diabetes 2008
Dysfunction
Summary of available
insulin preparations
Glucose lowering
Agent Type / Administration Basal Post-meal

NPH Intermediate-acting human

Once or twice daily at bedtime ± breakfast
Detemir Long-acting analogue

Once or twice daily at bedtime ± breakfast
Glargine Long-acting analogue

Once daily at bedtime or before breakfast
Premixed Human or analogue mix
 
Twice daily before breakfast and dinner
Regular Fast-acting human

Before meals
Aspart, Rapid-acting analogue
glulisine, lispro 
Before meals
Inhaled insulin Rapid-acting human

Before meals
Evidence insulin therapy
Sub Optimal Insulin Therapy
27 % of persons with type 2

diabetes use insulin therapy,
but less than one half
achieve the recommended
A1C level of 7 percent or less
Suboptimal insulin
therapy
Changes in treatment therapies for adults with type 2

diabetes mellitus based on National Health and Nutrition
Examination Survey (NHANES) results
Diabetes Care, Vol. 27, 2004;17-20

Step in Insulin Absorption
Normal Blood Glucose Levels
Blood Glucose (mmols)

10-
8-
6-
4-
2-
8am noon 6pm 2am 4am 8am
Time
Normal Blood Glucose Levels

10-
8-
6-
4-
2-
Time
10-
Two injections/day
8-
6-
4-
2-
R or H + N in AM R or H + N at Supper
0
Time
10-
Three injections/day
8-
6-
4-
2- R or H + N in R or H at N before bed
AM Supper
0
Time
www.diabetescl 46
10- Four injections/day

8-
6-
4-
2-
R or H at every meal N or U once or twice/day
0

Time
www.diabetescl 47
Continuous Infusion
10-
8-
6-
4-
2-
Time
What should I tell the person with Type
2 diabetes who needs
insulin, but doesn’t want to take it?
‘Insulin will not make your diabetes worse. In fact,

it will help control your glucose, so you’ll have
fewer complications and you’ll feel better.’
• Strict glycaemic control reduces the risks of both

microvascular and macrovascular complications
• People who start insulin usually feel much better
for it
I
N
Western regimen
S
Two doses: 150
U The usual dosing commonly used.

Initial insulin therapy
L 50
 
6 9 12 3 6 9 12 3
I
Three doses: 150
N Used for active patients.

Patients taking two main meals.
50
I
6 9 12 3 6 9 12 3
  
N Four doses: 150
Brittle diabetic patient.

J
Pregnant mothers specially type 1.
E
50
   
6 9 12 3 6 9 12 3
C
Four doses: 150
T Brittle diabetic patient.

I Motivated patients. 50
6 9 12 3 6 9 12 3
O   
N 
Multiple Insulin Injection Therapy

I
N
Western regimen
S
Two doses: 150
U The usual dosing commonly used.

Initial insulin therapy
L 50
 
6 9 12 3 6 9 12 3
I
Three doses: 150
N Used for active patients.

Patients taking two main meals.
50
I
6 9 12 3 6 9 12 3
  
N Four doses: 150
Brittle diabetic patient.

J
E
50
   
6 9 12 3 6 9 12 3
C
Four doses: 150
T Brittle diabetic patient.

I Motivated patients. 50
6 9 12 3 6 9 12 3
O   
N 
Multiple Insulin Injection Therapy

The 17 Beneficial Effect of Insulin
(Summerized : Tjokroprawiro 2007-2009)
1. Glicemic Control : ↓ A1C 10. ↑ Lipogenesis
2. Cardio-protection 11. Vaspin ↑
3. Anti-Atherosclerosis 12. Anti-Oxidant (↓ ROS)
4. Profibrinolisis 13. ↓ Plasma Arginase
(↓ PAI-1) (↓ Urea)
5. Anti-Thrombosis 14. ↑ Bone Anabolic
(↓Tissue Factor) (↑ Osteogenesis)
6. Anti-Platelet ( ↑ c-AMP) 15. ↓ ADMA in Plasma and
Endothelium
7. Vasodilatation 16. ↓ Lipolysis
(↑ NO, ↑ eNOS) (↓FFA Rel, ↓ TG,↑HDL-C)
8. Anti-Apoptosis 17. Restore LH, FSH,
(Heart, Brain, β Cell) (Testosteron)
9. Anti-Inflamation
(↑ IκB, ↓ NFκB, ↓MCP-1,
↓TNFα, ↓ ICAm-1, ↓CRP)
Dissociation of Regular Human Insulin
Regular Human Insulin
10-3 M 10-3 M 10-5 M 10-8 M peak time

2-4 hr
  
formulation hexamers dimers monomers
capillary membrane
Limitations of Regular Human Insulin
Advantages of Rapid-Insulin Analogues
Insulin Glargine
Long Acting-Insulin Analogue
OAD Interventions as monotherapy
During progression of disease, loss of glucose control with oral agents results in glucose toxicity
and worsening pathophysiology. In experimental models, prolonged exposure to hyperglycemia
has been shown to result in glucotoxicity and oxidative stress, culminating in β-cell destruction
and microvascular and macrovascular complications
The timely addition of insulin to oral agents can prevent this cycle of disease progression and
eliminate the “stuttering” pattern of loss of glycemic control.
What should I tell the person with Type
2 diabetes who needs
insulin, but will not take injections?
‘Most people who do not want to take injections are
happy using them after giving their first injection; but non-
injectable forms of insulin are also available now, and I
can show you both so you can choose.’
• Most people are amazed by how easy and painless

modern injections are
• Inhaled insulin before meals also gives good reductions
in HbA1c
• Treatment satisfaction improves with better blood
glucose control with both types of insulin administration
in people starting insulin
Inhaled Insulin
Dry Powder Inhaler for Pulmonary Insulin
Mealtime inhaled insulin substituted for
or added to combination oral agents
309 People on Combination Oral Agents
Baseline HbA1c 9.2% 9.3% 9.3%

0.0
-0.2%
-0.5
 HbA1c (%)
-1.0
-1.5 -1.4% INH+OA
* INH
OA
-2.0 -1.9%
*
INH = inhaled insulin; OA = secretagogue + metformin or TZD
*P<0.0001 vs OA
Rosenstock J et al. Ann Intern Med. 2005;143:549-558
Mealtime inhaled insulin or
metformin added to sulfonylurea
427 People on Sulfonylurea with HbA1c 8.0% to 12.0%
Baseline HbA1c 8.8% 8.8% 10.5% 10.6%
0.0
-0.5
 HbA1c (%)
-1.0
-1.5
-2.0 -1.8%
-1.9% -1.9%
INH + SU -2.2%
-2.5 P=0.002
Met + SU
HbA1c ≤9.5% HbA1c >9.5%

INH = inhaled insulin; Met = metformin; SU = sulfonylurea
Barnett AH et al. Diabetes Care. 2006;29:1282-1287
Patient satisfaction with inhaled vs SC
human insulin in an open-label study
121 People with Type 1 or Type 2 Diabetes
Overall
Satisfaction Ease of Use Social Comfort
P<0.01
 Treatment satisfaction (%)
50 P<0.01 NS
43.2%
37.9% 39.3%
40
30
20
8.7%
10
3.1%
0
-0.9%
-10 Inhaled insulin (n=60)
SC human insulin (n=61)
Rosenstock J et al. Diabetes Care. 2004;27:1318-1323

Dosing of dry powder
inhaled insulin
Dose Dose of Regular SC 1-mg Blisters per 3-mg Blisters
Insulin Dose per Dose
1 mg 3U 1 —
2 mg 6U 2 —
3 mg 8U — 1
4 mg 11 U 1 1
5 mg 14 U 2 1
6 mg 16 U — 2
Exubera (insulin human [rDNA origin]) inhalation powder [prescribing

information]. New York: Pfizer Inc; 2006
Hypoglycaemia and weight gain with
inhaled insulin in Type 2 diabetes
INH Comparator INH + Risk Ratio
Comparator (INH /
Comparator)
Rate of hypoglycaemia (overall events/subject-month)
INH vs SC human insulin 1.4 1.6 — 0.89

(CI 0.82-0.97)
INH vs rosiglitazone 0.7 0.05 — 15

(CI 8-29)
24
INH or INH + OA vs OA 1.3 0.1 1.7
(CI 14-42)*
Weight gain (lb)

INH vs SC human insulin 1.3 4.0 —
INH vs rosiglitazone 4.2 1.8 —
INH or INH + OA vs OA 6.2 0 6.0
*INH alone/OA. INH = dry powder inhaled insulin. OA = oral agents

DeFronzo RA et al. Diabetes Care. 2005;28:1922-1928. Hollander PA et al. Diabetes Care.
2004;27:2356-2362. Rosenstock J et al. Ann Intern Med. 2005;143:549-558
Treatment considerations with
inhaled insulin
• Pulmonary function changes with inhaled insulin are
clinically insignificant, nonprogressive, and reverse after
discontinuation of therapy
• Inhaled insulin is contraindicated in smokers, those who
have recently quit smoking, and those with asthma or
chronic obstructive pulmonary disease due to altered
pharmacokinetics
• Increased levels of insulin antibodies with inhaled insulin vs
SC human insulin
– Peak within 6-12 months and do not increase further
– Stop upon withdrawal of inhaled insulin
– No correlation between increased antibodies and changes in
insulin dose, HbA1c, or lung function
DeFronzo RA et al. Diabetes Care. 2005;28:1922-1928. Hollander PA et al. Diabetes Care.
2004;27:2356-2362. Rosenstock J et al. Ann Intern Med. 2005;143:549-558. Brain JD. Diabetes
Obes Metab. 2005;7:S14-S18. Fineberg SE et al. J Clin Endocrinol Metab. 2005;90:3287-3294.
Hirsch IB. Clinical Diabetes; 23;2; 2005
Insulin Pharmacodynamics:
NPH vs Ultralente vs Glargine vs CSII
The widespread decrease in glycemic control
Percentage of adults with diabetes who have achieved target glycemic, blood pressure,
and total cholesterol levels as reported in the National Health and Nutrition Examination
Surveys (NHANES III and NHANES 1999-2000).
J Am Osteopath Assoc. 2007;107:260-269
Stepwise Intensification of Treatment
for Continuity of Control

Insulin Therapy For Type 2 Diabetes Mellitus: Akhmad Nurdani

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Insulin Therapy for

Type 2 Diabetes Mellitus

Department of Internal Medicine

Impaired ß cell function:

Impaired insulin action:

• Results in unacceptable blood

Wild S, et al. Diabetes Care 27:1047–1053, 2004

RISKESDAS, 2007 : Prevalence DM 5,7%

Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25;

20 Loss ~4 % per year

UKPDS Study Group. Diabetes. 1995;44:1249-1258

• Both patients and physicians are often reluctant

• Insulin Therapy : The “Last Resort”

Breakfast Lunch Supper

Le Roith D , Zick Y Dia Care 2001;24:588-597

Figures of Approximate Pharmacokinetic Profiles of Human Insulin

The relative duration of action of the various forms of insulin is shown.

Glycaemic Control Hypoglycaemia (events pt-yr-1)

NPH insulin HbA1c (%)

(PG  3.1 mmol/l)

Biphasic aspart 70/30 Glargine

0600 0800 1200 1800 2400 0600

B = breakfast; L = lunch; D = dinner

More stringent HbA1c targets (e.g. 6.0–6.5% [42–48 mmol/mol]) :

• These risks can be minimized by

*Hypoglycaemia: temporary incapacity or requiring medical help

• Glycemic targets and glucose-lowering therapies must

Increased Increased Glucose

Agent Type / Administration Basal Post-meal

27 % of persons with type 2

Changes in treatment therapies for adults with type 2

Diabetes Care, Vol. 27, 2004;17-20

Blood Glucose (mmols)

8am noon 6pm 2am 4am 8am

Blood Glucose (mmols)

8am noon 6pm 2am 4am 8am

8am noon 6pm 2am 4am 8am

8am noon 6pm 2am 4am 8am

10- Four injections/day

8am noon 6pm 2am 4am 8am

8am noon 6pm 2am 4am 8am

‘Insulin will not make your diabetes worse. In fact,

• Strict glycaemic control reduces the risks of both

U The usual dosing commonly used.

N Used for active patients.

Brittle diabetic patient.

T Brittle diabetic patient.

Multiple Insulin Injection Therapy

U The usual dosing commonly used.

N Used for active patients.

Brittle diabetic patient.

T Brittle diabetic patient.

Multiple Insulin Injection Therapy

Regular Human Insulin

10-3 M 10-3 M 10-5 M 10-8 M peak time

• Most people are amazed by how easy and painless

Baseline HbA1c 9.2% 9.3% 9.3%

-1.5 -1.4% INH+OA

HbA1c ≤9.5% HbA1c >9.5%

Rosenstock J et al. Diabetes Care. 2004;27:1318-1323

Exubera (insulin human [rDNA origin]) inhalation powder [prescribing

INH vs SC human insulin 1.4 1.6 — 0.89

INH vs rosiglitazone 0.7 0.05 — 15