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Focus on Medications –Diabetes Now and Beyond

Dave Joffe, R.Ph, CDE, FACAConducted over 50 Diabetes Days at Eckerd, with help from Bayer, MiniMed ,Novo, Lilly, Lifescan, and Disetronic

Eckerd Patient Care Pharmacist 1999- 2000. Managed Patients full time in 3 Retail Locations. Responsible for 170 Diabetes Patients with Full Therapy Rights on Over 70 Patients.

President National AADE Pump specialty practice group

Diabetes Outcome Manager, currently managing over 200 diabetes patients in private practice, with primary care physicians. Certified Insulin

Pump trainer Deltec, Animas and Minimed

Editor in Chief Editor in Chief ––Diabetes In Control .comDiabetes In Control .com

Delivered CE To Over 12000 Medical Professionals

Past -President JDRF Tampa Bay Chapter

Past President Florida West Coast Assoc. Diabetes Educators

Relationship Between A1C and Average Blood Glucose

A1C (%) Average BG (mg/dL)

High Risk

for

Complications

Increasing Risk for

Complications

Good Control Less Risk for Complications

Normal Range Low Risk for

Complications

345

320

295

255

225

195

165

135

106

75

13

12

11

10

9

8

7

6

5

4

Data from Diabetes Control and Complications Trial (DCCT).

QUALITY OF PATIENT CARE

US Average 9.3 US Average 245mg/dl

ACE Goal 6.5

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Benefits of Reducing A1C by 1%

Type 1 Diabetes (DCCT)• ↓ 32% risk for retinopathy• ↓ 24 – 27% risk for nephropathy • ↓ 30% risk for neuropathy

• Type 2 Diabetes (UKPDS)• ↓ 10% in diabetes-related death• ↓ 6% in all-cause mortality• ↓ 18% risk for MI• ↓ 25% risk for microvascular complications DCCT Research Group. New England Journal of Medicine. 1993;329:977 UK PDS Group, Lancet. 1998;352:837.

Glucose Monitoring

Type 1- Frequent SMBG (at least three or four times per day)

Type 2- Should be sufficient to facilitate reaching glucose goals, utilizing fasting, ppbg and hs.

A1c test every 3 months

CGM : Continuous glucose monitoring

Average Type 2 checks 0.6 times a day and has 0.9 A1c tests each year.

Meter plugged into wall, sample more than 50 ul of blood- then washed off!!

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New Devices 2005

• Better Monitoring and Insulin delivery improve care

MiniMed Continious Glucose MonitorThink 4 fingerstick measurements are enough?

The Medtronic MiniMed Continuous Glucose Monitoring System -CGMS- gives you the information to see the complete picture. 288 glucose readings a day - up to 864 glucose readings over a 72-hour period. At work. At play. Asleep. A glucose measurement is automatically recorded -continuously- every 5 minutes

For the first time ever, your patients now have a continuous complete picture of what food, exercise and medication is doing to their glycemic levels.

The Future of Glucose Monitoring is Here TodayThe Future of Glucose Monitoring is Here Today

The Guardian CGMS

Do you think this is worth $1900 plus $35 every 3 days for a sensor

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16-year-old girl with HbA1C of 7.4%

Patient Data: Dave Joffe, BSPharm, CDE; USF Pediatric Endo Pump Patient, 2004

Poll Question

1

Same 16-year-old girl with HbA1C of 7.4% and CGMS

Patient Data: Dave Joffe, BSPharm, CDE; USF Pediatric Endo Pump Patient with Medtronic CGMS, 2004

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Poll Question

2

New Devices 2006

• Better Monitoring and Insulin delivery improve care, and it keeps getting better.

– Secretagogues• Sulfonylureas• Meglitinides

– Insulin Sensitizers• Biguanides• Thiazolidinediones (TZD)

– Intestinal Nutrient Absorption Modifiers• Alpha-Glucosidase Inhibitors (AGI)

– Hormone Replacement and Supplementation• Insulin and insulin analogs

MEDICATIONS FOR DIABETES TYPES AND MECHANISMS OF ACTION

1921- 2005

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Normoglycemia

Increased insulinsecretion

Decrease in hepaticglucose production

Increase in glucose uptakein fat and muscle

BiguanidesThiazolidinediones

SulfonylureasNon-sulfonylurea secretagogues

ThiazolidinedionesBiguanides

Alpha-glucosidaseinhibitors

Decreased digestion ofcomplex sugars

Sites/Mechanisms of Action of Antihyperglycemic Agents

Krenz et al. Drug Safety 1994;11:223-241.; Bloomgarden. Clinical Therapeutics 1998;20:216-231; Spiegelman. Diabetes 1998;47:507-514.; Saltiel et al. Diabetes 1998;445:1661-1669.American Diabetes Association. Diabetes Care 1995;18:1510-1518.

Treating to Target

Incretin Mimetics

Insulin Secretagogues: Mechanisms of Action1. Intestine:

glucose absorption2. Muscle and

adipose tissue:glucose uptake

3. Pancreas: Insulin secretionSulfonylureas

insulin secretion

4. Liver: hepatic glucose output

Insulin resistance

Insulin resistanceBlood glucose

Lebovitz HE. Joslin’s Diabetes Mellitus, Ch. 29, 508-529.

Treating to Target

Biguanides: Mechanisms of Action1. Intestine: glucose absorption 2. Muscle and adipose tissue:

Biguanides glucose utilization

3. Pancreas: insulin secretion

4. Liver: Biguanideshepatic glucose output

Insulin resistance

Insulin resistanceBlood glucose

DeFronzo et al. J Clin Endocrinol Metab 1991;73:1294-1301.Stumvoll et al. N Engl J Med 1995;333:550-554.

Treating to Target

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Thiazolidinediones:Mechanisms of Action

Muscle andadipose tissue↓ insulin resistance↑ glucose uptake

Liver↓ insulin resistance↓ hepatic glucose

production

Bloodglucose

Pancreas↓ demand for insulin secretion↑ beta-cell insulin content

Balfour, et al. Drugs 1999;57:921-930.Whitcomb, et al. From Diabetes Mellitus, Ch. 74, p. 661-668.

Treating to Target

Alpha-Glucosidase Inhibitors:Mechanisms of Action

1. Intestine: glucose absorption

2. Muscle and adipose tissue: glucose uptake

3. Pancreas: insulin secretion

4. Liver: hepatic glucose output

Insulin resistanceBlood glucose

Insulin resistance

Amatruda. From Diabetes Mellitus, Ch. 72,1996,p. 643-648.

Treating to Target

Poll Question

3

8

Patients with Type 2 Diabetes May Spend 12 Hours Per Day in the Postprandial State

Adapted from: Monnier L. Is postprandial glucose a neglected cardiovascular risk factor in type 2 diabetes? Eur J Clin Invest. 2000;30(suppl 2):3-11.

Duration of postprandial state

Breakfast Lunch Dinner Midnight 4 AM Breakfast

8AM 11AM 2PM 5PM

Postprandial Postabsorptive Fasting

Basal Treatment Program withPeakless Long-Acting Analogs Alone

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

Breakfast

LunchDinner

8:0012:008:00

Glargine

Plasma insulin (µU/mL)

75

50

25

0

Verbal communication from Bode, BW. Atlanta, Ga; Feb. 2003.

Meal time insulin response is missing, high postprandial readingsevery meal

Basal/Bolus Treatment Program withRapid-Acting and Peakless Analogs

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

Breakfast Lunch Dinner

8:0012:008:00

Glargine

Aspartor

Lispro

Aspartor

Lispro

Aspartor

LisproPlasma insulin (µU/mL)

75

50

25

0

Verbal communication from Bode, BW. Atlanta, Ga; Feb. 2003.

The Best But Requires 4 Injections

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Skyler J. In: Humes HD, Dupont HL, eds. Kelley’s Textbook of Internal Medicine. 4th ed. Philadelphia, Pa: Lippincott; 2000.

Basal/Bolus Affect of Insulin Absorption with Regular and NPH Insulin Preparations Injecting

with a Meal.

Plasma insulin (µU/mL)

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

Breakfast Lunch

Dinner

REGREG NPH

75

50

25

0

Severe Nocturnal hypoglycemiaSevere Inter-meal hypoglycemia

Increased risk for hypoglycemia especially at night

NPH

Skyler J. In: Humes HD, Dupont HL, eds. Kelley’s Textbook of Internal Medicine. 4th ed. Philadelphia, Pa: Lippincott; 2000.

Basal/Bolus Affect of Insulin Absorption with Aspart and Protamated Aspart Mixed Insulin Preparations Injecting with

a Meal.

Plasma insulin (µU/mL)

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

Breakfast Lunch Dinner

LISPlispPLISP

75

50

25

0

Lower Evening Dose less nocturnal hypoglycemia

PLISP

Rapid insulin for less postprandial hypoglycemia

The Best Method With The Easiest Compliance

Old Is New in 2006

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Poll Question

4

Practical Management of Type 2 Diabetes Mellitus

1. Hines SE. Intensive management of type 2 diabetes. Patient Care.April 30, 2000:91-107.2. Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72.

Add insulin

FPG > 126 mg/dL

“Self Management Education”MNT and Physical Activity

Monotherapy

140-240 mg/dL

Add Sulfonylurea

Add Insulin

140-240 mg/dL

Prior to 1995

Practical Management of Type 2 Diabetes Mellitus

1. Hines SE. Intensive management of type 2 diabetes. Patient Care.April 30, 2000:91-107.2. Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72.

GlitazonesMetformin

Alpha-glucosidaseinhibitors Add Sulfonylurea Add insulin

Oral Combination

• Adequate trial of monotherapy• FPG > 140 mg/dL• A1c > 7 %

• Add second oral agent and titrate to maximum dose

Triple Therapy

• If no improvement• Try different sensitizer• Or try triple therapy• Or continue oral agent(s) and add insulin

Rx at PM or HS

Sx = Symptoms

FPG > 126 mg/dL

“Self Management Education”MNT and Physical Activity

Monotherapy

200-240 mg/dL140-200 mg/dL120-140 mg/dL 300 mg/dL240-300 mg/dL

No Sx Sx No Sx/Sx No Sx Sx

From 1995 to 2005

•Plus Pharmacotherapy for Co-Morbidities

•11,300 possible combinations-diabetes alone

Sulfonylureas Metformin,GlitazonesRepaglinideAcarbose

Sulfonylureas Metformin,

Over 1350 new compounds in research for Diabetes, MetSyn, and Obesity

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2005 Brings 2 New Classes To Market

Glp-1

Amylin

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Excessive Glucose Fluctuations

Aafafafffaffaasfa

33

12

34

PostprandialGlucagon

Pancreas

Insulin

•Insulin helps regulate glucose

disappearance

Amylin

•Amylin helps regulate glucose

appearance

FoodIntake

—

GastricEmptying

—

Gut

GLP-1

35

36

Insulin-Using Type 2

Type 1

Without Diabetes

13

37

“One wonders if the development of a pharmacological means of suppressing glucagon to appropriate levels would not increase the effectiveness of available insulin, markedly reduce insulin requirements, and perhaps improve control of the diabetic state.”

— R.H. Unger

Values Before Insulin InfusionValues After Insulin Infusion

Insulin

38

5/16/2006 3:11:41 PM 39

14

40

41

42

15

43

44

45

16

46

Potential for Nausea at Initiation

15 µg

30 µg

45 µg

60 µg

Initiation

SYMLINEscalate Dose as Directed by HCP: After

3-7 Days if No Significant Nausea

47

17

GLP-1 secreted upon the ingestion of food

Long

BYETTA

BYETTA

Placebo

Placebo

18

19

Byetta Notes• Must be kept refrigerated (30 day shelf life once

started) and cannot be frozen.• Must be taken twice a day one-half hour before

breakfast and dinner. If you skip a meal it should not be taken for that meal.

• Not recommended for patients on insulin. Nor should patients be taken off of insulin and given Byetta.

• Most common side effect was mild to moderate nausea, which dissipated over time.

• A reduction in dose of sulfonylurea is recommended when Byetta is started.

2006 Brings New Classes To Market

Inhaled Insulin

DPP4 inhibitor

Exubera

Mean Glucose Infusion Rate (GIR) Normalized to GIRmax for Each SubjectTreatment Versus Time in Healthy Volunteers

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Safety and Efficacy

• The efficacy and safety profile of Exubera was studied in more than 2,500 adult patients with type 1 and 2 diabetes, for an average duration of 20 months.

• Exubera was found to be as effective as short-acting insulin, and to significantly improve blood sugar control when added to diabetes pills.

• In clinical trials, many patients using Exubera reported greater treatment satisfaction than patients taking insulin by injection. Significantly more patients who had used both Exubera and insulin injections or diabetes pills reported an overall preference for Exubera.

Indications and UsageEXUBERA is indicated for the treatment of adult

patients with diabetes mellitus for the control of hyperglycemia.

EXUBERA has an onset of action similar to rapid-acting insulin analogs and has a duration of glucose-lowering activity comparable to subcutaneously administered regular human insulin.

In patients with type 1 diabetes, EXUBERA should be used in regimens that include a longer-acting insulin.

CAUTION

• Because of the effect of EXUBERA on pulmonary function, all patients should have pulmonary function assessed prior to initiating therapy with EXUBERA. Periodic monitoring of pulmonary function is recommended for patients being treated with EXUBERA

• Should not be used in smokers unless they have stopped smoking for at least 6 months.

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Approximate Equivalent IU Dose of Regular Human Subcutaneous Insulin for EXUBERA Inhaled Insulin Doses Ranging from 1 mg to 6 mg

2-166 mg

12145 mg

11114 mg

1-83 mg

-262 mg

-131 mg

Number of 3 mgEXUBERA

Blisters per Dose

Number of 1 mgEXUBERA

Blisters per Dose

Approximate Regular

Insulin SC Dose in IU

Dose (mg)

Combine 1 mg and 3 mg blisters so that the least number of blisters per dose are taken.

Consecutive inhalation of three 1 mg unit dose blisters results in significantly greater insulin exposure than inhalation of one 3 mg unit dose blister. Therefore, three 1 mgdoses should not substituted for one 3 mg dose

Considerations for Dose Titration

• After initiating EXUBERA therapy, as with other glucose-lowering agents, dose adjustment may be required based on the patient’s need (e.g., blood glucose concentrations, meal size and nutrientcomposition, time of day and recent or anticipated exercise). Each patient should be titrated to their optimal dosage based on blood glucose monitoring results.

• As for all insulins, the time course of EXUBERA action may vary in different individuals or at different times in the same individual.

• EXUBERA may be used during intercurrent respiratory illness (e.g., bronchitis, upper respiratory tract infection, rhinitis). Close monitoring of blood glucose concentrations and dose adjustmentmay be required on an individual basis. Inhaled medicinalproducts (e.g. bronchodilators) should be administered prior to administration of EXUBERA.

How Supplied

xxxx-xxxx-xx90 x 3 mg

2 EXUBERA® Release UnitsEXUBERA 3 mg Patient Pack

xxxx-xxxx-xx90 x 1 mg

2 EXUBERA® Release UnitsEXUBERA 1 mg Patient Pack

xxxx-xxxx-xx

90 x 1 mg insulin blisters90 x 3 mg insulin blisters

2 EXUBERA® Release Units

EXUBERA 1 mg and 3 mgCombination Patient Pack

NDCContentsDescription

EXUBERA®(insulin human [rDNA origin]) Inhalation Powder is available as follows:

Not in-use (Unopened): Store at controlled room temperature, 77°F; Do not freeze. Do not refrigerate. In-use: Once the foil overwrap is opened, unit dose blisters should be protected from moisture, stored at 77°F; Do not freeze. Do not refrigerate. Unit dose blisters should be used within 3 months after opening the foil overwrap. Return the blisters to the overwrap to protect from moisture. Inhaler-1 year usage: Release Unit – 2 weeks

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Poll Question

5

DPP-IV inhibitor

• JANUVIA™• Sitagliptin is a medicine now under

development by Merck & Co. for the treatment of type 2 diabetes will be the first member of a new class of antihyperglycemic agents called DPP-IV inhibitors, which inhibit the DPP-4 enzyme that normally inactivates the incretin gut hormones GLP-1.

What Does The Future Hold?• New Insulins

– Oralin-Buccal Spray- Generex Bio Corp 2008 earliest, approved in Ecuador 5-2005

• GLP-1 agonists– LAF237, Novartis applied FDA 2003, US 2007 earliest

– Liraglutide, Novo applied FDA 2003, US 2007 earliest

– Merck 036 applied FDA 2004, US 2006 earliest

• Cmpd-1101, Innodia Inc, increases insulin secretion and decreases peripheral insulin resistance and is inactive at normal blood sugar concentrations, First human trials 2005, earliest 2009

• GLP1-INT, Novo, Transition Therapeutics, increases pancreatic insulin and beta cell mass to levels that approach normal levels, First human trials 2005, earliest 2008

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What’s in the anti-obesity pipeline?

• Acomplia, Rimonabant works on cannaboid receptors, but high drop out due to depressionexpected in 2007 New 17,000 patient study to start in July

• Axokine, like Xenical without side effects earliest in 2008. • PYY 3-36-, Nasal Spray Nastech, Merck hypothalamic control

of food, earliest 2011

• MCR-3 and MCR-4 agonists, decreases dietary fat intake, earliest 2012

• Stearoyl-CoA Desaturase-1,Xenon and Novartis, increases metabolic rate through lipid oxidation, First human trials 2006, earliest 2011

Who Can Help??

The Pharmacist– New Drug Information– Co-Morbidity Drug information– Side Effects– Drug Interactions– Medication Costs – Insurance Coverage– Food Interactions– Compliance– Insulin Training– Meter Training