incorporating inh for type2

8/9/2019 Incorporating INH for Type2

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During the presentation, various

inhaled human insulintreatments are also referred to

by brand name for purposes of

clarity only.


3/77

Behavioral Risk Factor Surveillance System, Centers for Disease Control and Prevention. Available at:http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/ andhttp://www.cdc.gov/diabetes/statistics/prev/state/. Accessed January 20, 2006.

Obesity

No Data


4/77

American Diabetes Association Diabetes Statistics. Available at:http://www.diabetes.org/diabetes-statistics.jsp. Accessed March 28, 2007.

Prevalence of Diabetes in People Aged 20

Years and Older in the US

20.8 million people (7.0% of population) have diabetes 10% of adult men; 8.8% of adult women

20.9% of people aged 60 years or older

>90% have type 2 diabetes

>6 million people are undiagnosed

1.5 million new cases of diabetes diagnosed annually

Almost 21 million Americans now have diabetes and more than 90% of thecases are type 2 diabetes. Included in this number are over 6 million peoplewho are not yet diagnosed. Almost 10% of the adult population and over20% of those 60 years of age or older have diabetes. About 1.5 million newcases of diabetes are diagnosed annually.


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6/77

In the diabetes control and complicationstrial (DCCT), the reduction of A1C from9.1% to 7.3% was accompanied by a

retinopathy reduction of __ %?

A. 9%

B. 63%

C. 36%

D. 77%


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* A1C goal for individual patient is as close to normal (


8/77

The ADA recommends that A1C levels are

assessed at least ___ times per year in

patients with type 2 diabetes whose A1C

levels are >7%.

A. One

B. Two

C. Three

D. Four


9/77

American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4-S41.

Nonglycemic Goals for Diabetes

Management

Hypertension Goal 1 other cardiovascular riskfactor(s)

Cigarette smoking goal Cessation

There are also goals for the treatment of blood pressure and dyslipidemia. The goal forblood pressure is less than 130/80 mm of mercury. The LDL cholesterol goal is less than100 mg/dL with less than 70 mg/dL being an option if patients also have existingcardiovascular disease. The HDL goal in men is greater than 40 mg/dL and in womengreater than 50 mg/dL and the goal for triglycerides is less than 150 mg/dL. Low dose

aspirin should be prescribed to adult patients with diabetes and macrovascular disease orfor primary prevention in those greater than the age of 40 years or who have additional riskfactors. Aspirin can be considered in people between the age of 30 and 40 years,particularly in the presence of other cardiovascular risk factors.


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CVD is a diabetes comorbidity and the major

cause of mortality in diabetes patients. Diabetes

patients who are treated more intensively

experience less CVD comorbidity. Nathan et al

were able to demonstrate that intensive treatment

can reduce CVD risk by ___%?

A. 18%B. 42%C. 78%D. 25%


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Saaddine JB, et al. Ann Intern Med. 2006;144:465-474.

So, how well are we meeting these goals?

Saaddine: 465a,466a,b


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Saaddine JB, et al. Ann Intern Med. 2006;144:465-474.

National Health and Nutrition ExaminationSurvey (19881994 and 19992002)

and Behavioral Risk Factor SurveillanceSystem (1995 and 2002)

Survey participants 18 to 75 years of age whoreported a diagnosis of diabetes

A recent paper by Saaddine and colleagues reviewed The National Health andNutrition Examination Survey between 1988 and 1994 and again from 1999 to 2002and also looked at the Behavioral Risk Factor Surveillance System reports from1995 and 2002. Survey participants were 18 to 75 years of age who reported adiagnosis of diabetes.

Saaddine: 465a,466a,b


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LDL


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Dyslipidemias are major contributors to CVD, the major

cause of mortality in diabetes patients. ADA

recommendations for LDL, triglyceride, and HDL levels

respectively in diabetic adults are ___mg/dL, __mg/dL,and __mg/dL?

A. 50 inwomen)

B. 50 in men)

C.


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A1C of 6% to 8% increased

from 34.2% to 47.0%

A1C >9%: 24.5% 20.6% NS

A1C


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Laboratory database analysis of >157,000 patients with type 2 diabetes

in 39 states showed 67% had A1C levels exceeding goal of6.5%

AACE. State of Diabetes in America: Striving for Better Control. Available at:http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf.Page 6. Accessed March 27, 2007.

State of Diabetes in America

AACE Report for 20032004

The American Association of Clinical Endocrinologists State of Diabetes inAmerica reported on a laboratory database analysis of over a 157,000patients with type 2 diabetes in 39 states. It showed that over two-thirds hadA1C levels exceeding the goal of 6.5% or less and in every state more thanhalf of the people were above this goal.

AACE state:3a, 6a


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Why Patients Dont Achieve Goal

Lack of optimal healthcare delivery systems Suboptimal use of diabetes education

Suboptimal patient adherence to lifestyle andpharmacologic treatments

Reimbursement issues

Failure of clinicians to adopt treat-to-targetapproach

Failure to advance therapy and especially toadd insulin in a timely manner

So, why don't patients achieve goal? Well, there is a lack of optimalhealthcare delivery systems and particularly suboptimal use of diabeteseducation, a crucial resource in the management of people with diabetes.There is suboptimal patient adherence to both lifestyle and pharmacologictreatments. There are a number of reimbursement issues and there is

failure of clinicians to adopt a treat-to-target approach and particularlysometimes the failure to advance therapy, and especially to add insulin in atimely manner. These all contribute to the failure to achieve goal.


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For patients using multiple daily insulin

injections, self-monitoring of blood

glucose should be conducted___ ?

A. Once daily

B. Twice daily

C. Every 12 hours

D. At least 3 times a day


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www.BetterDiabetesCare.nih.gov

From the NDEP

The National Diabetes Education Program has created a website,www.betterdiabetescare.nih.gov, to help clinicians better organize the care theydeliver to patients with diabetes using principles of the Chronic Care Model.


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Why Patients Dont Achieve Goal

Lack of optimal healthcare delivery systems

Suboptimal use of diabetes education

Suboptimal patient adherence to lifestyle andpharmacologic treatments

Reimbursement issues

Failure of clinicians to adopt treat-to-target approach

Failure to advance therapy and especially to addinsulin in a timely manner

So, lets focus on the fact that clinicians don't always adopt a treat-to-targetapproach and there is often a failure to advance therapy and especially toadd insulin in a timely manner.


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Therapy Is Not Modified* Soon Enough

8.2

7.7

8.8

7.6

7.1

9.1

5

6

7

8

9

10

Metforminmonotherapy

Sulfonylurea

monotherapy

A1C%

First A1C on

Treatment

Last A1C Before

Switch or Addition

35 Months**

27 Months**

ADA goal

AACE goal

Best A1C on

Treatment

0

*Monotherapy switched to another agent or additional agent added. **Meannumber of months that elapsed until a new or additional treatment was started.

Brown JB, et al. Diabetes Care. 2004;27:1535-1540.

Brown and colleagues conducted a prospective population-based study analyzingobservational data on over 7000 complete courses of diabetes treatment. Amongpeople on monotherapy with metformin or a sulfonylurea the first A1C on treatmentwas significantly above goal. Even the best A1C on monotherapy was above goal.The last A1C before a switch or addition of medication was 8.8% or greater and the

time from the best A1C to the last A1C average 27 to 35 months. The averagepatient accumulated nearly 5 years with an A1C above 8% from diagnosis untilstarting insulin and about 10 years with an A1C above 7% before starting insulin.

Brown: 1537a,b


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In spite of the fact that type 2 diabetes is a

progressive disease in which patients drug

regimens are likely to become more

complicated over time, the percentage of OADtreated patients is going up but the percentage

of insulin treated patients remains the same.

A. True

B. False


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Insulin Use in the US Remains UnchangedDespite Poor Control

Between NHANES III (1988-1994) and NHANES (1999-2000), the percentage of OA-

treated patients increased ~7%. NHANES, National Health and Nutrition ExaminationSurvey.

Adapted from: Koro CE, et al. Diabetes Care2004;27:17-20.

NHANES III (1988-1994) versus NHANES (1999-2000)

NHANES III (1988-1994) NHANES (1999-2000)

0

10

20

30

40

50

60

Patients(%)

Diet Only

27.4

20.2

OAs

45.452.5

OAs +

Insulin

3.1

11.0

Insulin Only

24.2

16.4

Constant: 27% of patients

treated with insulin

An analysis of NHANES III and NHANES 1999 through 2000 showed thatdespite the fact that most people failed to achieve goal glycemia, only 27% ofpatients were treated with insulin and that number had not increased during thetime interval between the 2 studies.


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Fear ofInjection

Permanenceof Having toTake Insulin

PersonalFailure inManagingDiabetes

Fear of theDemands of

Insulin Therapy

Inconvenienceof Monitoring

56.1%53.1%58.1%

55.0%50.8%

100

80

60

40

20

0

Patients(%)

Polonsky WH, et al. Diabetes Care. 2005;28:2543-2545.

Unwilling Patients: Barriers to

the Use of Insulin

Polonsky and colleagues asked people with diabetes to complete a questionnairedesigned to assess their attitudes toward taking insulin. Of the more than 1200diabetic patients who returned the questionnaire, 708 were people with Type 2diabetes who were not taking insulin. On the first question, which asked people torate their willingness to begin insulin therapy, almost 30% reported that they would

be unwilling to take insulin if it was prescribed. In the remaining questions, thosepeople who said that they were unwilling to take insulin identified fear of injectionand fear of the demands of insulin therapy, as well as concern that once startinginsulin it would have to be taken indefinitely forever--or that insulin therapy wouldmean that they had failed to do a good job, or that insulin monitoring would be tooinconvenient and restrictive as barriers to initiation of insulin.


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American Association of Clinical Endocrinologists (AACE)/American College ofEndocrinology (ACE) Road Maps:

www.aace.com

www.aace.com/meetings/consensus/odimplementation/roadmap.pdf

American Diabetes Association (ADA) Standards of Care and ConsensusAlgorithm for the Initiation and Adjustment of Antihyperglycemic Therapy

http://care.diabetesjournals.org/cgi/content/full/30/suppl_1/S4

Diabetes Care. 2006;29:1963-1972.

Texas Diabetes CouncilInsulin Algorithm for T2DM

www.dshs.state.tx.us/diabetes/PDF/algorithms/PHARM2.PDF

National Diabetes Education Program:

www.ndep.nih.gov

www.BetterDiabetesCare.nih.gov

Resources to Help Clinicians Achieve

Glycemic Targets

Free, non-copyrighted, reproducible patient education materials and resources tohelp healthcare professionals better understand and treat diabetes, including acomprehensive Medication Supplement.

On this slide I have aggregated a number of web resources that should be able tohelp clinicians better achieve glycemic targets. Included are the AmericanAssociation of Clinical Endocrinologist Road Maps, the new American DiabetesAssociation, European Association for the Study of Diabetes Consensus Algorithmfor Antihyperglycemic Therapy, an algorithm from the Texas Diabetes Council and

websites of the National Diabetes Education Program, a partnership of the NationalInstitutes of Health, the Centers for Disease Control and Prevention and more than200 public and private organizations working to change the way diabetes is treated.


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AACE Road Maps (www.aace.com)

ACE/AACE Diabetes Roadmap Task Force. Roadmap for the Prevention and Treatmentof Type 2 Diabetes. Available at:http://www.aace.com/meetings/consensus/odimplementation/roadmap.pdf. AccessedMarch 28, 2007.

The AACE Road Maps are a comprehensive guide to therapy for people with or atrisk for diabetes.


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Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.

The American Diabetes Association and the European Association for the Study ofDiabetes recently published a paper entitled Management of Hyperglycemia inType 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment ofTherapy.


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Anti-hyperglycemic Agentsin Type 2 Diabetes

ClassA1C

Reduction, % HypoglycemIaWeightchange

Dosing,

times/day

Insulin 1.5 to 2.5 Yes Gain1 to 4

injected

Sulfonylureas 1.5 Yes Gain 1

Glinides 1 to 1.5 Yes Gain 3

Biguanides (metformin) 1.5 No Neutral 2

Thiazolidinediones,glitazones

0.5 to 1.4 No Gain 1

Alpha-glucosidase inhibitors 0.5 to 0.8 No Neutral 3

Amylin-mimetics(pramlintide)

0.5 to 1.0 No Loss3

injected

Incretin agonists (exenatide) 0.5 to 1.0 No Loss2

injected

DPP-4 inhibitors 0.6 to 0.8 No Neutral 1

Adapted from Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.

Januvia [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2006.

The document reviewed the efficacy and safety of antihyperglycemic agents for thetreatment of type 2 diabetes. Some of the comments about these therapies areshown on this slide.


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A 45-year-old male type 2 diabetes patient taking

2 oral antidiabetic agents (OADs) for 2 years is in

for a check-up and has A1C of 8.5%, fastingpreprandial and 2-hour postprandial glucose of

180 and 220 mg/dL, respectively. Which

therapeutic initiative is preferred by the

American Diabetes Association (ADA/ EASD

consensus algorithm statement)?

A. Add third OAD

B. Initiate insulin therapy

C. Intensify diet and exercise interventionD. Switch OAD


30/773

Management of Hyperglycemia in Type 2 Diabetes

Diagnosis

Lifestyle Intervention + Metformin

A1C 7%No Yes*

Add Basal Insulin Most effective

Add Sulfonylurea Most effective

Add Glitazone No hypoglycemia

Intensify Insulin# Add Glitazone+ Add Basal Insulin# Add Sulfonylurea

Add Basal or Intensify Insulin#

Intensive Insulin+ Metformin +/- Glitazone

A1C 7%No Yes*A1C 7%No Yes

A1C 7%No Yes

A1C 7%No Yes*

A1C 7%No Yes

*Check A1C every 3 months until


31/773

Insulin in Management of

Hyperglycemia in Type 2 Diabetes

Nathan DM, et al. Diabetes Care2006;29:1963-1972.

Insulin is the most effective of the availablediabetes medications for lowering glycemia

It can, when used in adequate doses, decreaseany level of elevated A1C to, or close to, thetherapeutic goal

Unlike the other blood glucose-loweringmedications, there is no maximum dose ofinsulin beyond which a therapeutic effect willnot occur

The importance of insulin is emphasized by the consensus statement, which notedthat insulin is the most effective of the available diabetes medications for loweringglycemia. It can, when used in adequate doses, decrease any level of elevatedA1C to or close to the therapeutic goal. Unlike the other blood glucose loweringmedications, there is no maximum dose of insulin beyond which a therapeutic effect

will not occur.


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Triple Therapy in Type 2 Patients

Adapted from: Rosenstock J, et al. Diabetes Care. 2006;29:554-559.

A1C(%)

Time

(weeks)

9

8.5

8

7.5

7

6.5

4 8 12 16 20 24

Insulin glargine

Rosiglitazone

Mean A1C Levels From

Baseline to End Point

70

Changefromb

aseline

InA1C(%)

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

7.5 8 8.5 9 9.5 10 10.5 11

Insulin glargine

Rosiglitazone

Glycemic Control by Baseline A1C

Time (weeks)

When people with diabetes do not achieve goal despite a combination of 2 oralagents, one can initiate additional agents. In this study patients not at goal despitetreatment with metformin and a sulfonylurea were randomized to receive theaddition of either the thiazolidinedione rosiglitazone or insulin glargine, a basalinsulin. Similar glycemic control was achieved with both regimens. But when the

results were stratified by baseline A1C, insulin glargine showed better efficacy inthose individuals whose A1C at baseline was 9.5% or higher.


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Initiation of Insulin in Patients With

Type 2 Diabetes


If lifestyle, metformin, and a second medication do not resultin goal glycemia, the next step should be to start, or intensify,insulin therapy.

When A1C is close to goal (8.0%), addition of a third oralagent could be considered;

However, this approach is relatively more costly andpotentially not as effective in lowering glycemia comparedwith adding or intensifying insulin.

The consensus statement noted that if lifestyle, metformin, and a secondmedication did not result in goal glycemia, the next step should be to start orintensify insulin therapy. When A1C is close to goal, around 8% or less, addition ofa third oral agent could be considered. However, in the opinion of the consensusstatement, this approach is relatively more costly and potentially not as effective in

lowering glycemia compared with adding or intensifying insulin.


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Eventually Most Type 2 Diabetes

Patients Are Likely to Require Insulin

Therapy

Eventually, most type 2 diabetes patients are likely to require insulin therapy.


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Insulin Administration Should Attempt

to Emulate Endogenous Insulin Profiles

Seen in Non-diabetic Individuals

When using insulin one should attempt to emulate endogenous insulin profiles seenin non-diabetic individuals.


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Basal/Bolus Insulin Absorption Pattern

With Standard Insulin Preparations

Adapted from: Skyler J. In: Humes HD, Dupont HL, eds. Kelleys Textbook ofInternal Medicine. 4th ed. Philadelphia, Pa: Lippincott; 2000.

PlasmaInsulin(U/mL)

Time

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

NPH

LunchBreakfast Dinner 75

50

25

0

Slide 3-22

When a non-diabetic individual eats a meal, they get a burst of insulin thatcontrols their postprandial or post-meal glucose. Between meals andovernight there is a low but steady level of basal insulin that maintainsglucose values in the normal range. NPH insulins are not ideal basalinsulins. They tend not to last 24 hours and their glycemic profiles exhibit

peaks rather than maintaining a uniform or flat level of insulin throughouttheir activity period. Failure to last 24 hours can result in periods ofhyperglycemia, while the peak insulin levels can be associated with anincreased risk for hypoglycemia.


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Adapted from: Skyler J. In: Humes HD, Dupont HL, eds. Kelleys Textbook of InternalMedicine. 4th ed. Philadelphia, Pa: Lippincott; 2000.

Time

PlasmaInsulin(U/mL)

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

75

NPH

LunchBreakfast Dinner

50

25

0

GLARGINE/DETEMIR

Slide 3-22

Insulin glargine and insulin detemir are better basal insulins and better mimicbasal insulin secretion that occurs in non-diabetic individuals. These arebasal insulin analogues that tend to last up to 24 hours and they have aflatter insulin profile that is more uniform.


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Time

PlasmaInsulin(U/mL)

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

75

NPH


50

25

0

GLARGINE/DETEMIR

Slide 3-22

Similarly, regular human insulin peaks too late and lasts too long to be anoptimum mealtime insulin.


39/773




PlasmaInsulin(U/mL)

Time4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

NPH

GLARGINE

INH INH


Lispro/Aspart/

Glulisine

Lispro/Aspart/

Glulisine

75

50

25

0

INHLispro/Aspart/

Glulisine

Slide 3-22

Injectable rapid-acting insulin analogs, insulin lispro, insulin aspart, andinsulin glulisine have a much more rapid onset and offset of action and bettermimic endogenous mealtime insulin secretion that occurs in non-diabeticindividuals. Similarly, inhaled insulin has a more rapid onset of action than(subcutaneously) injected regular human insulin.


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Basal Insulin Therapy

Controls glycemia between mealsand overnight

QD or BID administration

Options:

Long-acting insulin analogs(glargine, detemir)

Human insulin (NPH)

Cefalu WT, et al, eds. The CADRE Handbook of Diabetes Management. 1stEdition. New York, NY: Medical Information Press; 2004.

Basal insulin therapy controls glycemia between meals and overnight. Itusually involves daily or twice daily administration. One can use the long-acting insulin analogs, insulin glargine, and insulin detemir. One could alsouse human NPH insulin.


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8.5

9.0

8.0

7.5

7.0

6.5

0 4 8 12 16 20 24

A1C(%)

NPH + OAD

Glargine + OAD

Weeks

Once-daily Glargine vs NPH inTreat-to-Target Trial: A1C and Hypoglycemia

NPH neutral proamine hagadorn; OAD oral anti-diabetic (therapy)

Adapted from: Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.

0

2

4

6

8

10 44% risk

reduction

P


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Twice-daily Detemir vs NPH inTreat-to-Target Trial: A1C and Hypoglycemia

Adapted from: Hermansen K, et al. EASD 2004. Poster 754:PS 64.

55% risk

reduction

P


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Post-prandial Glucose Contribution to A1C

A1C Range (%)

Fasting plasma

glucose (FPG)

Post-prandial

glucose (PPG)

Adapted from: Monnier L, et al. Diabetes Care2003;26:881-885.

30

70

>10.2

Contribution(%)

0

20

40

60

80

100

9.3-

10.2

8.5-9.2

70

30

60

40

55

45

7.3-

8.4

50

50


44/774

Pre-mixed Insulin Therapy

Contains both prandial and longer acting insulin Usually administered 2 or more times per day

Options:

70/30 NPH/regular insulin

70/30 protamine aspart (NPA)/aspart insulin

75/25 protamine lispro (NPL)/lispro

50/50 protamine lispro (NPL)/lispro

Cefalu WT, et al, eds. The CADRE Handbook of Diabetes Management. 1stEdition. New York, NY: Medical Information Press; 2004; Hirsch IB. Medscape GenMed. 2005;7:49. Available at: http://www.medscape.com/viewarticle/515847.Accessed March 28, 2007.

Premixed insulin therapies contain both prandial and longer-acting insulin,they are usually administered 2 or more times per day. The various optionsare shown on this slide.


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Goal Achievement With Biphasic Insulin

Aspart 70/30: The 1-2-3 Study

ITT Population (N = 100)

Adapted from: Garber AJ, et al. Diabetes Obes Metab. 2006;8:58-66.

A1C 6.5% A1C


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Premixed Insulin

May be simpler approach to initiating insulin in patients withpoorly controlled (PG >8.5%)

Difficult to achieve A1C


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Prandial, Bolus, or Pre-meal Insulin

Addresses hyperglycemia after meals Administered 1 to 3x/day

Options

Short-acting (regular) injectable insulin

Rapid-acting (aspart, lispro, glulisine) injectableinsulin analogs

Inhaled insulin

Cefalu WT, et al, eds. The CADRE Handbook of Diabetes Management. 1st Edition.New York, NY: Medical Information Press; 2004.

One can address postprandial hyperglycemia more specifically by using aprandial bolus or premeal insulin. These are administered 1 to 3 times a daybefore meals, the options are short-acting regular human injectable insulin,rapid-acting insulin aspart, insulin Lispro, insulin glulisine, which areinjectable insulin analogs, or inhaled insulin.


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Insulin Time-Action Profile

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480 540 600

MaximalGluc

ose

InfusionRate

(%)

Time (min)

Lispro

Regular

Inhaled

Adapted from: Rave K, et al. Diabetes Care. 2005;28:1077-1082.

This slide shows glucose infusion rates as a measure of the time course ofinsulin action in healthy volunteers. Rapid-acting insulin analog lispro has amore rapid onset of glucose lowering activity than subcutaneously injectedregular human insulin. Exubera, the first FDA-approved inhaled insulin hasan onset of glucose-lowering activity within 10 to 20 minutes, and maximum

effect in about 2 hours similar to what is seen with injected insulin lispro.The duration of glucose lowering activity with Exubera is comparable to thatof subcutaneously injected human insulin.


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0

2

4

6

8

10

12

0 1 2 3 4 5 6 7 8 9 10

Pfizer/Aventis/Nektar

Time (h)

Glucose infusion rates (mg/kg/min)

Aerogen

Lilly/AIR/Alkermes

MannKind

Technosphere

Novo Nordisk/Aradigm

15 U Lispro s.c.

Data from different studies

KOS

GIR

Adapted from: Heinemann L, et al. Br J Diab Vasc Dis.2004;4:295-301.

Time-Action Profile of Inhaled Insulin

This slide shows the insulin time action profiles of lispro and Exubera, as wellas several other inhaled insulin products that are presently underdevelopment but not yet FDA approved. All but 1 have similar time actionprofiles to that of Exubera. The MannKind Technosphere insulin producthas a more rapid onset and offset of action than the others.


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Adding Prandial Insulin to Basal Insulin


If A1C above goal when FBG in target range (70-130 mg/dL),

check BG pre-lunch, dinner, and bed; depending on BGresults, add second injection with rapid acting insulin; can

usually begin with ~4 units and adjust by 2 units/3 days until BGin range

Pre-lunch BG aboverange add RAI at

breakfast

Pre-dinner BGabove range add

RAI at lunch

Pre-bedtime BGabove range add

RAI at dinner

BG - blood glucose; FBG fasting blood glucose; RAI rapid-acting insulin

The ADA-EASD algorithm recommends that if the A1C remains above goal, oncethe fasting glucose is in the target range, that one should perform SMBG beforelunch, dinner, and bedtime; and depending on these results add a second injectionusing rapid-acting insulin. One can usually begin with about 4 units and adjust by 2units every 3 days until the blood glucose is in range. So if the pre-lunch SMBG is

above range, one can add rapid-acting insulin at breakfast. If the pre-dinner SMBGis above range, one should add rapid-acting insulin at lunch. And if the pre-bedtimeSMBG is above range, one can add rapid-acting insulin at dinner. One could alsouse inhaled insulin in these circumstances as a prandial insulin now that it isavailable.


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Basal Bolus Insulin Regimen

Basal insulin administered QHS, QAM or BID Preferably using long acting insulin analog

Prandial insulin administered before meals

Preferably using rapid acting insulin analog orinhaled insulin

Basal insulin adjusted to control FPG

Prandial insulin adjusted to control PPG

With the addition of pre-meal insulin, we evolve to a basal bolus insulin regimenwhere the basal insulin is administered at bedtime, in the morning or twice a daypreferably using a long-acting insulin analog. The prandial insulin is administeredbefore meals preferably using rapid-acting insulin analog or inhaled insulin. Thebasal insulin is adjusted to control the fasting plasma glucose. The prandial insulin

is adjusted to control the post prandial glucose.


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Barriers to Basal/Bolus Insulin Therapy

Patients and physicians may have little experience with it andbelieve it is too complex

Requires diabetes self-management education support whichmay not be readily available

Requires multiple daily administrations of insulin

Requires performance of SMBG multiple times/day

The barriers to initiation of basal bolus insulin therapy include the fact that patientsand physicians may have little experience with it and believe its too complex, itrequires diabetes self management education support which may not always bereadily available, it requires multiple daily administrations of insulin and requiresperformance of SMBG multiple times per day.


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Benefits of Basal/Bolus Insulin Therapy

Improved glycemic control Greater flexibility in timing and quantity of meals

and activity

Reduced risk for hypoglycemia

Less likelihood of weight gain

Patient can be empowered to take control ofinsulin therapy adjustments

So, the benefits of basal bolus insulin therapy can be improved glycemic control,greater flexibility in timing and quantity of meals and activity, a reduced risk forhypoglycemia, less likelihood of excessive weight gain and the patient can be taughtand be empowered to take control of their insulin therapy adjustments.


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Prandial insulin therapy is usually

initiated after basal insulin treatment

However, prandial insulin can be used to

first initiate insulin therapy

Prandial insulin therapy is usually initiated after basal insulin treatment.However, prandial insulin can be used to first initiate insulin therapy.


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Targeting Postprandial Glucose

Lowers A1C

11

10

9

8

7

A1C

(%)

P= 0.003

P = 0 .025 P = 0 .445

11

10

9

87

6

Fasting

Blo

odGlucose

(mmol/L)

P< 0.001

P= 0.108 P= 0.029

2-hourPostprandial

GlucoseExcursion

(mmol/L)

P< 0.001

P< 0.001 P= 0.1334

3

2

1

0 L+G M+G NPH+G

Treatment Groups

14

13

12

11

10

9

8

P= 0.052

P= 0.009 P= 0.454

2-hour

PostprandialGlucose

(mmol/L)

L+G M+G NPH+G

Treatment Groups

Adapted from: Bastyr EJ, et al. Diabetes Care. 2000;23:1236-1241.

A

DC

B

M + G = Metformin + GlyburideNPH + G = NPH Insulin + Glyburide

L + G = Lispro + Glyburide

In this study by Bastyr and colleagues, 135 type 2 diabetes patients notadequately controlled with oral sulfonylurea agents alone were randomlyassigned for 3 months to 1 of 3 combination regimens with glyburide. Theseregimens were the addition of NPH insulin to glyburide at bedtime, the addition ofmetformin to glyburide or the addition of insulin lispro before meals with glyburide.One can see that the best control of fasting blood glucose occurred with theregimen that combined NPH insulin and glyburide. However the combination ofpremeal or prandial insulin lispro with glyburide resulted in the best control of two-

hour post prandial glucose. The best control of 2-hour postprandial glucoseexcursion and the best control of A1C, so the addition of a prandial insulin can bean effective way to initiate insulin therapy but many patients might be reluctant togo from no injections of insulin a day to 3 injections a day.


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Mealtime Inhaled Human Insulin* Substituted for

or Added to Combination Oral Agents309 Patients on Combination Oral Agents With A1C 8%

* Exubera; Pfizer Inc. [New York, New York], sanofi-aventis Groupe [Paris, France], and NektarTherapeutics [San Carlos, California]). INH = inhaled insulin; OA = secretagogue + metformin orthiazolidinediones; P


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Inhaled Insulin

Newest approved form of insulin

Prandial rapid onset insulin

Delivered by pulmonary inhalation

Inhaled insulin, or Exubera, is the newest approved form of insulin. It is a prandialrapid onset insulin that is delivered by pulmonary inhalation.


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Pulmonary Insulin Delivery System

(Pfizer/Nektar)

Exubera is a product of an alliance between Pfizer and Nektar Therapeutics and thepulmonary insulin delivery system consists of dry powder human insulin particlesthat are packaged in blisters that are then inserted in to the delivery device.Mechanical pressure turns this into a cloud of insulin particles that are then inhaledinto the deep lung and rapidly absorbed into the bloodstream.


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Other Inhaled Insulins in Development

Alkermes AIR

Particle Technology BreathActuated Pulmonary Insulin Delivery System(Lilly)

Aradigm AERx iDMS Pulmonary InsulinDelivery System (Novo-Nordisk)

TechnosphereTM Pulmonary Insulin DeliverySystem (Mannkind)

Breath Actuated Inhaler Pulmonary InsulinDelivery System (Kos)

Other inhaled insulins are presently in development. These include theLilly/Alkermes Air Particle Technology System, the Novo-Nordisk/Aradigm AERxiDMS System, The MannKind Technosphere Pulmonary Insulin Delivery System,and the KOS Breath Actuated Inhaler Pulmonary Insulin Delivery System.


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Effectiveness of Pulmonary

Delivery of Insulin

What is the effectiveness of pulmonary delivery of insulin?


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Screening Baseline 6 12 24

SC insulin (n=145)Inhaled insulin (n=143)

5

6

7

8

9

10

Duration of Treatment (weeks)

MeanA1C(%)

Type 2 Diabetes: Inhaled Insulin andConventional Insulin Therapy

Change in A1C

Adapted from: Hollander PA, et al. Diabetes Care. 2004;27:2356-2362.

In this study, type 2 diabetes patients who had previously been treated withsubcutaneously injected insulin were randomized to 6 months treatment witheither premeal inhaled insulin plus a bedtime dose of ultralente insulin or atleast 2 daily subcutaneous injections of mixed regular and NPH insulin. Youcan see that the glycemic control achieved with the 2 insulin regimens were

similar, and the goal of this study was to show that inhaled insulin wouldwork as well as conventional insulin therapy.


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0

10

20

30

40

50

Patients(%)


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Change in FPG With Inhaled Insulin

Adapted from: Hollander PA, et al. Diabetes Care. 2004;27:2356-2362

-10

0

Inhaled Insulin (Exubera)(n = 146)

SC regular insulin(n = 149)

-20

-30

-40

-60

-50

P=0.003

-22

-6

AdjustedMeanChange

FromB

aselineFPG(mg/dL)

In this study, the reduction in fasting plasma glucose was greater with the Exuberaregimen than with the regimen that used subcutaneous regular insulin before meals.In this trial some of this difference might be attributed to the fact that the basalinsulin was different between the 2 regimens but in other trials involving Exuberawhere the basal insulin was the same in the 2 comparator groups, there was still

better reduction of the fasting plasma glucose in the Exubera treated patients and agreater reduction in fasting plasma glucose then one might anticipate with a mealtime insulin that is given for the last time with the evening meal prior to the nextdays fasting plasma glucose.


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12 Week Trial of AERx vs SC Insulin

in Type 2 Diabetes Subjects

Adapted from: Hermansen K, et al. Diabetes Care. 2004;27:162-167.

9.0

8.5

8.0

7.5

7.0

0AERx SC AERx SC

Week 0 Week 12

Mean A1C before and after 12 weeks of treatment (intention-to-treat population).There was no difference in the change in A1C between the groups (P=0.60)

In this study, type 2 diabetes patients were randomized to receive either inhaled fastacting human insulin using the AERx iDMS System immediately before meals orsubcutaneously injected fast acting human insulin given 30 minutes before mealsboth in combination with evening NPH insulin. One can see that glycemic controlachieved with the 2 insulin regimens were similar, and in fact the goal of the inhaled

insulin trials has been to show that inhaled insulin would work as well assubcutaneously injected insulin.


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Technosphere Inhaled Insulin in Type 2 Diabetes

Adapted from: Rosenstock J. et al. ADA 66th Scientific Sessions.June, 2006 Washington, DC: Abstract 357 OR.

-0.76

P=0.0019 vs

placebo

-0.32Mean A1C

Change

7.74%7.75%A1C at

Baseline

Technosphere

Insulin

Technosphere

Placebo


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Inhaled Insulin in Type 2 Diabetes Not

Controlled With Diet and ExerciseAbsolute Change in A1C

6

7

8

9

10

11

Screening Baseline 6 12 Week 12

(LOCF)

MeanA1C(%)

Duration of Treatment (weeks)

Inhaled insulin (n=76)Rosiglitazone (n=69)

Adapted from: DeFronzo RA, et al. Diabetes Care. 2005;28:1922-1928.

Adjusted

mean

difference:

0.89%

What about using inhaled insulin as initial pharmacologic therapy in peoplewith type 2 diabetes who are not controlled with lifestyle measures, diet, andexercise? This study compared initiation of inhaled insulin with the use ofrosiglitazone in such patients. Twelve weeks is probably not long enough tosee the optimal effect of rosiglitazone; nevertheless, one sees a very robust

improvement in glycemic control in patients treated with inhaled insulin orExubera.


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Inhaled Insulin in Type 2 Diabetes Not

Controlled With Diet and ExerciseTreatment to Goal A1C (%)

Patients(%)

Adapted from: DeFronzo RA, et al.Diabetes Care. 2005;28:1922-1928.

Inhaled insulin

Rosiglitazone

0

10

20

30

40

50

60

7080

90P=0.0003


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Safety of Pulmonary Delivery of Insulin

What do we know about safety of pulmonary delivery of insulin?


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Incidence of Hypoglycemia With Inhaled InsulinType 1 and Type 2 Diabetes

0.050.7INH vs rosiglitazone

1.70.11.3INH or INH + OA vs OA

1.61.4

Type 2 diabetes

INH vs SC insulin

9.08.6

Type 1 diabetes

INH vs SC insulin

Inhaled Insulin+ Comparator(events/sub-

ject/month)

Comparator(events/sub-ject/month)

Inhaled Insulin(events/sub-

ject/month)

DeFronzo RA, et al. Diabetes Care. 2005;28:1922-1928; Hollander PA, et al.Diabetes Care. 2004;27:2356-2362; Quattrin T, et al. Diabetes Care. 2004;27:2622-2627; Rosenstock J, et al. Ann Intern Med. 2005;143:549-558.

As with all insulins, there is some risk for hypoglycemia with inhaled insulin.On this slide, one sees that the incidence of hypoglycemia in both type 1 andtype 2 diabetes patients is similar when one compares inhaled insulin to theuse of subcutaneously injected insulin. There is some increase in riskcompared to treatment with oral antidiabetic agents but there is also in these

trials better glycemic control with inhaled insulin than patients treated withthe oral regimens.


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Adapted from: Fineberg SE, et al. J Clin Endocrinol Metab. 2005;90:3287-3294.

Insulin Antibody Binding Responses After InhaledInsulin vs Comparator (SC Insulin or Oral Agents)

in the Initial Studies

20

40

60

0

InsulinAntibodies(median%

binding)

n=362 n=370 n=363 n=355 n=146 n=145 n=137 n=137 n=302 n=195 n=302 n=189

Noninsulinusing Type 2Patients

Insulin-using Type 2Patients

Type 1 Patients

Inhaled insulin SC insulin

Baseline

End ofStudy

+ +

+

+ + ++

+ + + + +

Baseline

End ofStudy Baseline

End ofStudy

+ = mean % bindingThe top and bottom bars represent the 75th and 25th percentile, respectively.

Insulin antibodies may develop during treatment with all insulin preparations including insubcutaneous regular insulin increases in insulin antibody levels were significantly greaType 2 diabetes. No clinical consequences of these antibodies were identified over thedeclined when Exubera was discontinued.


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Resolution of Treatment Group Differences

in FEV1 in Type 2 Diabetes (104-week

Cohort)Difference in Slopes (L/y)

Exubera vs Comparator 6-24

Months

0.000 (95% Cl: -0.032, 0.033)

Adapted from: Dreyer M. Diabetologia. 2004;47(suppl 1):A44.

Weeks

Comparative Phase Washout Phase

Exubera Oral AgentChangeFromB

aselinein

FEV

1(L)(meanSD)

-0.2

0

-0.4

0.2

24 36 52 65 78 91 104 +6 +12

Difference: -0.039 (95% Cl: -0.093, 0.015)

N=304

This slide looks at the change from baseline in FEV1

for patients treated either withExubera or oral agents over a 2-year period of time. In clinical studies, patientstreated with Exubera experienced greater declines in FEV1 and DLCO thancomparator-treated patients. The changes occurred early--within the first severalweeks of therapy. But as shown on this slide, for the remainder of the 2-year period

of time, there was no progressive difference. You see that the slope between theExubera-treated patients and the comparator-treated patients is the same after thefirst 24 weeks. The changes were small in magnitude--about 40 mLs at 2 years andmean FEV

1compared to a baseline that was approximately 3 liters. These changes

reversed 6 weeks after discontinuation of therapy in patients with type 2 diabetes.These changes were not driven by outliers, and the change from baseline in bothFEV

1and DL

COdid not correlate with the total daily dose or cumulative dose of

Exubera.


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Inhaled Insulin Safety Profile: Cough

Cough questionnaire Cough tended to occur within seconds tominutes after administering inhaled insulin

Cough was predominately mild

Cough was rarely productive and rarelyoccurred at night

Incidence of cough decreased withcontinued inhaled insulin use

In controlled clinical studies, 1.2% ofpatients discontinued inhaled insulintreatment because of cough

EXUBERA [US package insert]. New York, NY: Pfizer Labs; 2006.

Patients treated with Exubera more frequently exhibited cough than those treatedwith comparator. The cough tended to occur within seconds to minutes. AfterExubera inhalation it was predominantly mild, was rarely productive and rarelyoccurred at night. The incidence of cough decreased with continued Exubera useand 1.2% of patients discontinued Exubera treatment because of cough.


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T1DM Treatment Group Differences in FEV1 and

DLCO Carbon Monoxide Diffusing Capacity

InhaledSC

Adapted from: Skyler J, et al. Diabetes Care. 2007;30:579.

0.3

0.2

0.1

0

-0.1

-0.2

-0.3

-0.4

-0.5

3 6 9 12 15 18 21 24 24

LOCFMonthsChangefromb

aselinein

FEV,

(meanSD

)

Group Differenceat Month 3

=-0.021

Group Difference atMonth 24 LOCF

=-0.023

3

2

1

0

-2

-3

-4

-5

-6

3 6 9 12 15 18 21 24 24

LOCF

Group Differenceat Month 3

=-0.687

Group Difference atMonth 24 LOCF

=-0.439

4

-1

Change

fromb

aselinein

DLB

(mL/min/mmHg)

(m

eanSD)

Baseline

BaselineMonths

Here we see data from a very recently published study by Skyler andcolleagues looking at type 1 diabetes patients and treatment group differencesbetween those treated with Exubera and Comparator subcutaneously injectedinsulin in type 1 individuals looking at both FEV1 and DLCO. Treatment groupdifferences in lung function between Exubera and subcutaneous insulin in

adult patients with type 1 diabetes were small, developed early, and were non-progressive for up to 2 years of therapy similar to what we just saw in the type2 patients.


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Overall Treatment Satisfaction in Patients WithType 2 Diabetes: INH (Exubera) vs SC Insulin

Adapted from: Testa MA, et al. ADA 62nd Annual Meeting. Abstract 544-P. 2002.

Mean Satisfaction Scores at Baseline and Change at Month 6

NOTE: Standardized Treatment Satisfaction Scale ranges from 0 to 100; P


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Availability of Inhaled Insulin and

Acceptance of Insulin Therapy

Adapted from: Freemantle N, et al. Diabetes Care. 2005;28:427-428.

INH available Standard therapy only

00 1010 2020 3030 4040 5050Proportion of Patients (%)

15.515.5

35.335.3

7.97.9

43.343.3

27.427.4

INH

SC Insulin

No ChangeP< 0.0001

Will the availability of inhaled insulin enhance acceptance of insulin therapy amongpatients with type 2 diabetes? This study in which I was an investigator involvedalmost 800 patients in 7 countries with type 2 diabetes. All of the patients wereabove their glycemic goals. Patients were randomized into 2 groups; both groupsreceived information about what the therapeutic glycemic goal was, why it was

important to get to goal, and what are the conventional therapies that could beadded to their regimen. One group also received information about the potentialavailability of inhaled insulin. The patients and their healthcare professionals thenmade a joint theoretical choice of which therapy they would choose including theoption of making no change. Prior to the study, in the opinion of their physicians,about 50% of the patients should have gone on insulin as the next step. Whathappened in response to the study? For patients who only had access to standardtherapy, only about 16% chose to go on insulin. In contrast, nearly 3 times as manypatients chose insulin if inhaled insulin was potentially available and most of thesepatients chose inhaled insulin. Interestingly although none of the patients were atgoal, over 43% of patients who had access to standard therapy only chose to makeno change in their regimen and that number was significantly reduced to 27%among the patients who had the potential availability of inhaled insulin. This wasactually a feasibility trial and the actual study has now been done and in factpatients as opposed to this feasibility trial actually went on the therapy, they choseand were followed for 6 months and these results hopefully will become available inthe not too distant future.


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Improving the Care of People With Type

2 Diabetes

Overweight, obesity, insulin resistance,metabolic syndrome, pre-diabetes, and diabetesare epidemic in our society

Most people with type 2 diabetes do not achievetreatment targets

Most patients will eventually need insulin; butimplementation of insulin is often delayed

Pulmonary inhalation of insulin is effective andappears safe

Inhalation of insulin might facilitate earlierinsulin use and better glycemic control

So, in conclusion overweight, obesity, insulin resistance, pre-diabetes, and diabetesare epidemic in our society. Most people with type 2 diabetes do not achievetreatment targets. Most people will eventually need insulin but implementation ofinsulin is often delayed. Pulmonary inhalation of insulin is effective and appearssafe. Inhalation of insulin might facilitate earlier insulin use and better glycemic

control.


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