New Insulins and

Insulin Delivery Systems

Bruce W. Bode, MD, FACE

Atlanta Diabetes Associates

Atlanta, Georgia

Methods For Managing Persons with Diabetes

Take Diabetes out of the equation.

Control glucose!!!

Undiagnosed diabetes

~5.2 million

Prevalence of Glycemic Abnormalities in the United States

Additional 25 -35 million

with Prediabetes

Diagnosed type 2 diabetes

~12 million

Diagnosed type 1 diabetes

~1.0 million

Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm; Harris MI. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK; 1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001

US Population: 275 Million in 2000

3

Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.

Diabetes Care. 2001;24(Suppl 1):S5-S20.

FPG

126 mg/dL

100 mg/dL

7.0 mmol/L

5.6 mmol/L

Prediabetes

NormalNormal

2-Hour PG on OGTT

200 mg/dL

140 mg/dL

11.1 mmol/L

7.8 mmol/L

Diabetes MellitusDiabetes Mellitus

Impaired Glucose Tolerance

NormalNormal

Diabetes MellitusDiabetes Mellitus

Diagnostic Criteria Associated with Glucose Abnormalities

Relative Risk of Progression of Diabetes Complications (DCCT)

DCCT Research Group, N Engl J Med 1993, 329:977-986.

1

3

5

7

9

11

13

15

6 7 8 9 10 11 12

Retinop

Neph

Neurop

RELATIVE RISK

Mean A1C

Gain of 15.3 years of complication free living compared to conventional therapy

Gain of 5.1 years of life compared to conventional therapy

Lifetime Benefits ofIntensive Therapy (DCCT)

DCCT Study Group, JAMA 1996, 276:1409-1415.

Effect of A1C On Complications in the UKPDS Study

A1C

Stratton IM et al. BMJ 2000;321:405

0

10

20

30

40

50

60

Myocardial Infarction Microvasc Disease

5.5%6.5%7.5%8.5%9.5%10.5%

Lessons from the DCCT and UKPDS:Lessons from the DCCT and UKPDS:Sustained Intensification of Therapy is DifficultSustained Intensification of Therapy is Difficult

DCCT EDIC(Type 1)

UKPDS (Type 2),Insulin Group

DCCT/EDIC Research Group. New Engl J Med 2000; 342:381-389Steffes M et al. Diabetes 2001; 50 (suppl 2):A63UK Prospective Diabetes Study Group (UKPDS) 33Lancet 1998; 352:837-853

4

6

8

10

9.0

8.1

7.3

7.9

0 6.5 + 4 + 6 yrs

DCCT EDIC

0

6

7

8

0 2 4 6 8 10 yrs

A1C (%)

Normal

Baseline

A1C (%)

Specific Goals in Management of Diabetes

Fasting < 110 mg/dL

Post-meal < 140 mg/dL

A1C < 6.5%

Blood Pressure < 130/80

LDL < 100 mg/dL; HDL > 45 mg/dL

Triglycerides < 150 mg/dL

Primary Objectives of Effective Management

A1C%

SBPmm Hg

LDLmg/dL

45 50 55 60 65 70 75 80 85 90

9

Diagnosis

8

7

130

100

145

140

Patient Age

Reduction of both

micro- and macro-vascular

event rates

…by 75%!

lGæde P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl

J Med. 2003;348:383-393.

0

2

4

6

8

10

12

14

16

<150 150-175 175-200 200-225 225-50 >250

Average Post-operative glucose (mg/dl)

Mo

rtali

ty

Cardiac-related mortalityNoncardiac-related mortality

Mortality of DM Patients Undergoing CABG

Furnary et al J Thorac Cardiovasc Surg 2003;123:1007-21

0

5

10

15

20

25

30

35

40

45

0 50 100 150 200 250

Days after inclusion

Cum

ulat

ive

% M

orta

lity

(in h

ospi

tal d

eath

)

P=0.0009

P=0.026

BG<110

110<BG<150

BG>150

Surgical ICU MortalityEffect of Average BG

Van den Berghe et al (Crit Care Med 2003; 31:359-366)

05

1015202530354045

80-99 100-119

120-139

140-159

160-179

180-199

200-249

250-299

>300

Average ICU glucose (mg/dl)

Mo

rtal

ity

%

Hyperglycemia and Hospital Mortality1826 consecutive ICU patients 10/99 thru 4/02, Stamford CT

Krinsley JS: Mayo Clin Proc 78: 1471-1478, 2003

Glucose Goals in Type 2 DiabetesGlucose Goals in Type 2 Diabetes

• Fasting < 110 mg/dL

• Post-meal < 140 mg/dL

• A1C < 6.5%

Glucose Goals in Type 1 DiabetesGlucose Goals in Type 1 Diabetes

• Fasting and Premeal 70 - 140 mg/dL

• Post-meal < 160 mg/dL

• A1C < 6.5%

Glucose Goals in Hospital

80 – 110 mg/dl in Surgical ICU patients

80 - 140 mg/dl premeal and < 180 mg/dl postmeal in other Surgical and Medical Patients

70 – 100 mg/dl in Pregnancy

Insulin

The most powerful agent we have

to control glucose

Patient J.L., December 15, 1922 February 15, 1923

The Miracle of Insulin

Progression of Type 1 Diabetes

Adapted from: Atkinson. Lancet. 2002;358:221-229.

Age (y)

Precipitating Event

Be

ta-c

ell

ma

ss

Genetic predisposition

Normal insulin release

Glucose normal

Overt diabetes

No C-peptidepresent

Progressive loss of insulin release

C-peptidepresent

AntibodyAntibody

Options in Insulin Therapy for Type 1 Diabetes

Current

– Multiple injections

– Insulin pump (CSII)

Future

– Implant (artificial pancreas)

– Transplant (pancreas; islet cells)

Type 2 Diabetes … A Progressive Disease

Over time, most patients will need insulin

to control glucose

Multiple factors may drive progressive decline of -cell function

-cell(genetic background)

Hyperglycaemia(glucose toxicity)

Proteinglycation

Amyloiddeposition

Insulin resistance

“lipotoxicity”elevated FFA,TG

Approach to Combination Oral Therapy

Intensifying of Oral Therapies

metformin &/or glitazone+

sulfonylurea/repaglinide&/or glucosidase inh

sulfonylurea/repaglinide&/or glucosidase inh

+metformin &/or glitazone

Continue

FPG < 120 mg/dl A1C < 6.5% FPG > 120 mg/dl A1C >6.5%

Add Insulin

Comparison of Human Insulins / Analogues

Insulin Onset of Duration ofpreparations action Peak action

Regular 30–60 min 2–4 h 6–10 h

Lispro/aspart 5–15 min 1–2 h 4–6 h

NPH/Lente 1–2 h 4–8 h 10–20 h

Ultralente 2–4 h Unpredictable 16–20 h

Glargine 1–2 h Flat ~24 h

Dissociation & Absorption of Aspart / Lispro

Insulin Aspart or Lispro

Regular Human Insulin

Peak Time = 80-120 min

Peak Time = 40-50 min

CapillaryMembrane

Su

bcu

tan

eou

s T

issu

eS

ub

cuta

neo

us

Tis

sue

400

350

300

250

200

150

100

MealSC injection

50

00 30 60

Time (min)90 120 180 210150 240

Regular Lispro

500450400350300250

150

50

200

100

00 50 100

Time (min)150 200 300250

Pla

sm

a i

ns

uli

n (

pm

ol/

L)

Pla

sm

a i

ns

uli

n (

pm

ol/

L)

MealSC injection

Heinemann, et al. Diabet Med. 1996;13:625–629; Mudaliar, et al. Diabetes Care. 1999;22:1501–1506.

Short-Acting Insulin AnalogsLispro and Aspart Plasma Insulin Profiles

Regular Aspart

Lepore, et al. Diabetes. 1999;48(suppl 1):A97.

6

5

4

3

2

1

00 10

Time (h) after SC injection

End of observation period

20 30

GlargineNPH

Glu

cose

uti

lizat

ion

rat

e(m

g/k

g/h

)

Glargine vs NPH Insulin in Type 1 DiabetesAction Profiles by Glucose Clamp

4:004:00

2525

5050

7575

8:008:00 12:0012:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

Pla

sma

insu

lin

(P

lasm

a in

suli

n (µ U

/ml)

U

/ml)

TimeTime

8:008:00

Physiological Serum Insulin Secretion Profile

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Glargine

Lispro Lispro Lispro

Aspart Aspart Aspartor oror

Pla

sma

insu

lin

Basal/Bolus Treatment Program withRapid-acting and Long-acting Analogs

The Basal/Bolus Insulin Concept

Basal insulin

– Suppresses glucose production between meals and overnight

– 40% to 50% of daily needs

Bolus insulin (mealtime)

– Limits hyperglycemia after meals

– Immediate rise and sharp peak at 1 hour

– 10% to 20% of total daily insulin requirement at each meal

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

Starting With Basal Insulin in DM 2Advantages

1 injection with no mixing

Insulin pens for increased acceptance

Slow, safe, and simple titration

Low dosage

Effective improvement in glycemic control

Limited weight gain

6-37

Treatment 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 < 100 mg/dL

- if 100-120 mg/dL, increase 2 units

- if 120-140 mg/dL, increase 4 units

- if 140-180 mg/dL, increase 6 units

- if >180 mg/dL, increase 8 units

Treatment to Target Study; A1C Decrease

8.6

7.5

7.16.9 7

6.5

7

7.5

8

8.5

9

0 5 10 15 20 25 30

Weeks in Study (N=691)

Mea

n H

bA

1c%

Treatment to Target Study: % at Goal

57% of patients in both groups reached A1C 7%

At wk 24, mean insulin glargine dose was higher than mean NPH insulin dose:

Insulin glargine NPH insulin

48.8 IU/day 42.4 IU/day , P<0.001

Rosenstock J, Riddle M, HOE901/4002 Study Group. Diabetes 2002;51(suppl 2):A482. Abstract 1982-PO

Results

Treat to Target Study: Glargine vs NPH Added to Oral Therapy of Type 2 Diabetes

Nocturnal Hypoglycemia reduced by 40% in the Glargine group (532 events) vs NPH group (886 events)

Riddle et al, Diabetes June 2002, Abstract 457-p

Morning vs Bedtime InsulinMorning vs Bedtime Insulin

Baseline: 9.11.0

Morning Glargine

Bedtime Glargine

Bedtime NPH

-2

-1

0

A1C

Ch

ang

e F

rom

B

asel

ine

(%)

–1.24

–0.96–0.84

P<0.001

P=0.008

Adapted from Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952

Starting with Bolus Insulin

16 obese Type 2 patients on NPH or Human 70/30 insulin twice daily randomized to:

Insulin aspart premeal with metformin and rosiglitazone

NPH or Human 70/30 twice daily

Insulin titrated to 90 to 126 mg/dl at 1.5 hr post meal in the aspart group and premeal in the conventional group with goal A1C <7%

Diabetes Care 2003

Insulin Aspart Premeal with Metformin and Rosiglitazone vs Conventional Insulin

5

6

7

8

9

10

Insulin Aspart Premeal NPH or 70/30 BID

Baseline

6 months

A1C%

N =16

0.42 units/kg

3 kg weight gain

0.67 units/kg

1 kg weight gain

P = 0.03

Advancing Basal/Bolus Insulin

Indicated when FBG acceptable but– A1C > 7% or > 6.5%

and/or– SMBG before dinner > 140 mg/dL

Insulin options– To glargine or NPH, add mealtime aspart / lispro– To suppertime 70/30, add morning 70/30– Consider insulin pump therapy

Oral agent options– Usually stop sulfonylurea– Continue metformin for weight control– Continue glitazone for glycemic stability?

Novo Nordisk devices in diabetes care

First pen (NovoPen 1) launched in 1985

Committed to developing one new insulin administration system per year.

Lilly Insulin Pens

Prefilled Syringe with Flexible Dosing

82%

2%

16%

Prefer FlexPen

Prefer Humalog pen

No preference

82% of DNEs Preferred FlexPen®

Source: Diabetes Nurse Educators In-Depth Study—Reactions to FlexPen.

NovoLog® FlexPen®

®

Novo Innolet®

Large push button with low resistance

Large-scale numbers

1 unit increments

Support shoulder

Maximum dose 50 units

Clear & uncomplicated dial, dials forward and back

Contains 300 units Novolin® 70/30, NPH, or R

Audible clicks

NovoFine® disposable needle

Needle storage compartment

Starting MDI

Starting insulin dose is based on weight

0.2 x wgt. in lbs. or 0.45 x wgt. in kg

Bolus dose (aspart/lispro) = 20% of starting dose at each meal

Basal dose (glargine/NPH) = 40% of starting dose at bedtime

Starting MDI in 180 lb person

Starting dose = 0.2 x wgt. in lbs.

0.2 x 180 lbs. = 36 units

Bolus dose = 20% of starting dose at each meal

20% of 36 units = 7 units ac (tid)

Basal dose = 40% of starting dose at bedtime

40% of 36 units = 14 units at HS

Individually determined

CIR = (2.8 x wgt in lbs) / TDD

Anywhere from 5 to 25 g CHO is covered by 1 unit of insulin

Estimating the Carbohydrate to Insulin Ratio (CIR)

Correction Bolus (Supplement)

Must determine how much glucose is lowered by 1 unit of short- or rapid-acting insulin

This number is known as the correction factor (CF)

Use the 1700 rule to estimate the CF

CF = 1700 divided by the total daily dose (TDD)

ex: if TDD = 36 units, then CF = 1700/36 = ~50

meaning 1 unit will lower the BG ~50 mg/dl

Correction Bolus Formula

Example:

–Current BG: 220 mg/dl

– Ideal BG: 100 mg/dl

–Glucose Correction Factor: 50 mg/dl

Current BG - Ideal BGGlucose Correction factor

220 - 100 50

=2.4u

Options to MDI

A Simpler Regimen

Insulin Pump

Premixed BID (DM 2 only)

Human Insulin Time-action Patterns

Time (h)

Baseline

level

Regular insulin

Premix 70/30

SC injection

Normal insulin secretionat mealtime

NPH insulin

Ch

ang

e in

ser

um

in

suli

n

A More Physiologic Insulin

Time (h)SC injection

Baseline

Level

Normal insulin secretion at mealtime

NPH insulin

NovoLog

NovoLog Mix 70/30

Ch

an

ge

in s

eru

m in

su

lin

Analog Mix 70/30: Serum Insulin Levels in Type 2 Diabetes

Breakfast Lunch

06:00 PM 10:00 PM 8:00 AM 6:00 PM1:00 PM

Dinner

Cmax

Se

rum

ins

ulin

(m

U/L

)

100

Time

80

40

20

60

* * NovoLog® Mix 70/3070/30 Premix

McSorley. Clin Ther. 2002;24(4):530-539.

*P<0.05.

Analog Mix 70/30 vs 75/25 vs 70/30 Premix: Serum Insulin Levels in Type 2 Diabetes

Lispro Mix 75/25

70/30 Premix

Aspart Mix 70/30

0 1 2 3 4 50

80

Time (h)

Se

rum

ins

ulin

(m

U/L

)

60

40

20

Hermansen. Diabetes Care. 2002;25(5):883-888.

Aspart Mix 70/30:Serum Glucose Levels in Type 2 Diabetes

Aspart Mix 70/3070/30 Premix

Dinner Breakfast Lunch

*

0

300

200

150

250

Se

rum

glu

co

se (

mg

/dL

)

6:00 PM 10:00 PM 8:00 AM 6:00 PM1:00 PM

**

*Glucose excursions 0-4 h, P<0.05.McSorley. Clin Ther. 2002;24(4):530-539.

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

8:008:0012:0012:008:008:00

TimeTime

Basal infusion

Bolus Bolus Bolus

Pla

sma

insu

lin

Pla

sma

insu

lin

Variable Basal Rate: CSII Program

Photograph reproduced with permission of manufacturer.

Pump Infusion Sets

CSII vs MDI in 100 DM 1 Patients

Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438.

Mean ± 2 SEM

200

160

140

120

100

180

Se

lf-m

on

ito

red B

G (

mg

/dL

)

BB AB BL AL BD AD Midnight 3 AM

CSII (n=93)

MDI (n=91)

n=63 in each treatment

0

500

1000

1500

2000

2500

3000

CSII MDI

p = 0.0027

Novo Nordisk, data on file (Study 2155/US)

Aspart (CSII) vs Aspart/Insulin glargine (MDI) Glucose Exposure During CGMS

Measurement of AUC(glu) ≥80 mg/dL during the 48-hour continuous glucose monitoring period

†

AUCglu (mg•hr/dL)

†

6

6.5

7

7.5

8

8.5

9

Baseline 4 weeks 8 weeks 12 weeks 16 weeks

Glargine (n=16)

CSII (n=14)

CSII vs. MDI with Glargine in Children (Preliminary Data)

Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192.

A1c

CSII vs MDI in Children – Preliminary Data Safety and Preference

SafetySevere hypoglycemic episodes

MDI: 4CSII: 2

No cases of DKA

Preference (at 16 weeks)All 12 CSII subjects remained on CSII12 of 14 MDI subjects switched to CSII

Boland et al., Diabetes 2003, 52:S1, A45, 192-OR

CSII vs MDI with NPH in 127 DM 2 Patients

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

CSII MDI

Baseline

End of study (24 weeks)

Raskin et al. Diabetes Care Sept 2003

A1C

(%

)

Change in scores (raw units) from baseline to endpoint

-5 0 5 10 15 20 25 30 35

Convenience

Less burden

Less hassle

Advocacy

Preference

General satisfaction

Flexibility

Less life interference

Less pain

Fewer social limitations

MDICSII

CSII vs MDI in DM 2 Patients

Testa et al. Diabetes. 2001;50(suppl 2):1781

Current Pump Therapy Indications

Diagnosed with diabetes (even new onset DM 1)

Need to normalize blood glucose (BG)

–A1C > 6.5%

–Glycemic excursions

Hypoglycemia

Monitoring– A1C = 8.3 - (0.21 x BG per day)

Recording 7.4 vs 7.8

Diet practiced– CHO: 7.2– Fixed: 7.5– WAG: 8.0

Insulin type (Aspart)

CSIIFactors Affecting A1C

Bode et al. Diabetes 1999;48 Suppl 1:264

Bode et al. Diabetes Care 2002;25 439

• Total Daily Dose = 0.23 x Wgt. In lbs.

• Basal Dose = 0.47 x Total Daily Dose

• CIR = (2.8 x Wgt in lbs) / TDD

(Anywhere from 5 to 25 g CHO is covered by 1 unit of insulin)

• Correction Factor = 1700 / TDD

• Target = 100 mg/dl

Pump Formulas

Davidson et al: Diabetes Tech & Therap. April 2003

Individually determined

• CIR = (2.8 x wgt in lbs) / TDD

• Anywhere from 5 to 25 g CHO is covered by 1 unit of insulin

Estimating the Carbohydrate to Insulin Ratio (CIR)

Davidson et al: Diabetes Tech & Therap. April 2003

Bolus: Source of Errors

“Inability” to count carbs correctly

– Lack of knowledge, skill

– Lack of time

– Too much work

Incorrect use of SMBG number

Incorrect math in calculation

“WAG” estimations

Most common bolusing errors

Under-estimation of carbohydrates consumed (CHO bolus)

Over-correction of post-prandial elevations (CF bolus)

– Remaining unused, active insulin

– Stacking of boluses

The Major Problems

♦ Up until now we have not taken the active insulin issue into consideration

♦ The math involved with this has become too complicated, and it would be impossible to accurately calculate the active insulin without assistance

Smart Insulin PumpsSmart Insulin Pumps

Monitor sends BG value to pump via radio waves : No transcribing error

Enter carbohydrate intake into pump

“Bolus Wizard” calculates suggested dose

Paradigm Link™

Paradigm 512™) ) ) ) ) ) ) ) ) )

) ) )

Bolus Wizard Calculator : meter-entered

For This System To Work

♦ It is critical the target, basal doses, the correction doses, and the carbohydrate ratios are accurate

♦ Understanding how to match carbohydrate amounts with insulin is critical

♦ If the target is set too high (>110 mg/dl), glucoses will run too high. Normal target is 100 mg/dl and for pregnancy 80 mg/dl is safe.

Do Smart Pumps Enable Others To Go To CSII?

YES

All patients with diabetes not at goal are candidates for Insulin Pump Therapy

- Type 1 any age

- Type 2

- Diabetes in Pregnancy

If A1C is Not to Goal

SMBG frequency and recording

Diet practiced

– Do they know what they are eating?

– Do they bolus for all food and snacks?

Infusion site areas

– Are they in areas of lipohypertrophy?

Other factors:

– Fear of low BG

– Overtreatment of low BG

Must look at:

If A1C Not to Goal and No Reason Identified

Place on a continuous glucose monitoring system (CGMS by Medtronic Minimed, Glucowatch by Cygnus) to determine the cause

CGMS

CGMS Sensor

GLUCOSE MONITORING SYSTEMS - Telemetry

“Real time” glucose readings

Wireless communication from sensor to monitor

High and low glucose alarms

FDA panel pending

Consumer Product

GlucoWatch® Biographer

FreeStyle NavigatorTheraSense Continuous Glucose Monitor

• Patient Inserted Sensor

• “On demand” glucose and trend arrow

• User-configurable Low Glucose and High Glucose Alarms

• Projected alarms give advance warning of glucose excursions

• Integrated FreeStyle blood glucose meter

• (3) BG calibrations for each 3-day sensor

• Wireless sensor-to-Meter path (10 foot operating range)

FreeStyle NavigatorTheraSense Continuous Glucose Monitor

–Designed to monitor interstitial fluid and provide continuous glucose readings–Patient-attached adhesive section includes sensor, and wireless transmitter–Designed to be self-inserted every three days and provide patients with glucose for use in managing therapy

The DexCom Continuous Glucose Sensor System

Sensor

– 7 x 1 cm

– Cylindrical

– 7 cc

– Battery

– Microprocessor

– Antenna

Receiver

– Pager-Like Receiver with Graphical Display

Implantable Pump

Average HbA1c 7.1%

Hypoglycemic events reduce to 4 episodes per 100 pt-years

Implanted Closed-Loop External Closed-Loop

Vision towards the Artificial Pancreas

* This product concept not yet submitted to the FDA for commercialization.

Predicted Times

Glucose Sensors

- Alarm sensor (72 hr) early 2004

- Replace fingersticks mid late 2005

Semi-Closed loop 2006 – 2007

Implantable 2007-2008

Summary

Insulin remains the most powerful agent we have to control diabetes

When used appropriately in a basal/bolus format, near-normal glycemia can be achieved

Newer insulins and insulin delivery devices along with glucose sensors will revolutionize our care of diabetes

Billing Get paid for what you do

Use your codes and negotiate for coverage

Detailed visit: 99214

Prolonged visit with contact plus above: 99354 or 99355

(insulin start or pump start)

Prolonged visit w/o contact plus above:

99358 or 59 (faxes, phone calls, emails)

Billing

Bill faxes as prolong visits with out contact or negotiate a separate charge

Bill meter download: 99091

Bill CGMS: 95250

Bill immediate A1C: 83036

Questions

For a copy or viewing of these slides, contact

WWW.adaendo.com