The Next Generation: Exploring Current and Emerging ... · guidelines and evolving pharmacotherapy to optimize management of type 2 diabetes. ... Summarize current and emerging trends

The Next Generation: Exploring Current and Emerging Therapies for

Type 2 Diabetes

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The Next Generation: Exploring Current and Emerging Therapies for Type 2 Diabetes

A G E N D A

6:15 a.m. – 6:45 a.m. Registration and Breakfast 6:45 a.m. – 6:50 a.m. Welcome – Introductory Remarks

Susan Cornell, Pharm.D., CDE, FAPhA, FAADE 6:50 a.m. – 7:40 a.m. The Next Generation: Exploring Current and Emerging

Therapies for Type 2 Diabetes 7:40 a.m. – 7:45 a.m. Questions & Answers

F A C U L T Y

Susan Cornell, Pharm.D., CDE, FAPhA, FAADE Assistant Director of Experiential Education and Associate Professor of Pharmacy Practice Midwestern University Chicago College of Pharmacy Downers Grove, Illinois

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D I S C L O S U R E S T A T E M E N T

In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support and the Accreditation Council for Pharmacy Education’s Guidelines for Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on presentations. All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an educational activity. The faculty and planners report the following relationships: Susan Cornell, Pharm.D., CDE, FAPhA, FAADE

Dr. Cornell declares that she serves on the speakers bureau for Johnson & Johnson, Diabetes Institute, and Abbott Diabetes Care. Scott R. Drab, Pharm.D., CDE, BC-ADM

Dr. Drab declares that he is a consultant for Novo Nordisk and Roche Diagnostics. Kristi N. Hofer, Pharm.D.

Dr. Hofer declares that she has no relationships pertinent to this activity. Erika Thomas, M.B.A., B.S.Pharm.

Ms. Thomas declares that she has no relationships pertinent to this activity. Susan R. Dombrowski, M.S., B.S.Pharm.

Ms. Dombrowski declares that she has no relationships pertinent to this activity. ASHP staff has no relevant financial relationships to disclose.

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A C T I V I T Y O V E R V I E W

The Centers for Disease Control and Prevention estimates that 1 out of every 10 adults in the United States (U.S.) has diabetes, and if current trends continue, as many as 1 in 3 will have diabetes by 2050. Approximately 7 million people remain undiagnosed, and nearly 79 million Americans have pre-diabetes, which places them at high risk for developing diabetes. Diabetes is the seventh leading cause of death in the U.S. The estimated total financial cost of diabetes in the U.S. in 2007 was $174 billion, which includes the costs of medical care, disability, and premature death. Appropriate treatment and management of diabetes is critical to decrease the risk of complications associated with the disease. To achieve this goal, primary prevention, testing and early diagnosis, access to care for all persons with diabetes, and improved quality of care are necessary. Health-system pharmacists need to remain informed of updated treatment guidelines and evolving pharmacotherapy to optimize management of type 2 diabetes. A C T I V I T Y O B J E C T I V E S

At the conclusion of this application-based educational activity, participants should be able to

Discuss recent changes to national guidelines for the management of type 2 diabetes.

Compare and contrast traditional and new diabetes pharmacotherapy.

Describe emerging pharmacotherapy treatments for type 2 diabetes.

Summarize current and emerging trends in diabetes care.

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C O N T I N U I N G E D U C A T I O N A C C R E D I T A T I O N

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0 hour (0.1 CEU) of continuing pharmacy education credit (ACPE activity #0204-0000-12-442-L01-P). Attendees must complete a Continuing Pharmacy Education Request online

and may immediately print their official statements of continuing pharmacy education credit at the ASHP CE Center at http://ce.ashp.org following the activity. Complete instructions for receiving your statement of continuing pharmacy education online are found at the front of the CE in the Mornings handout booklet. Be sure to record the SESSION CODE beginning with “A” announced during the activity.

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Susan Cornell, Pharm.D., CDE, FAPhA, FAADE Assistant Director of Experiential Education and Associate Professor of Pharmacy Practice Midwestern University Chicago College of Pharmacy Downers Grove, Illinois Susan Cornell, Pharm.D., CDE, FAPhA, FAADE, is Assistant Director of Experiential Education and Associate Professor, Department of Pharmacy Practice at Midwestern University Chicago College of Pharmacy in Downers Grove, Illinois. Dr. Cornell is also a certified diabetes educator and clinical pharmacy consultant, specializing in community and ambulatory care practice. Dr. Cornell has over 24 years of practice in community pharmacy where she has practiced as a clinical pharmacist, diabetes educator, and preceptor, as well as the inaugural coordinator of the American Diabetes Association (ADA)-recognized Dominick’s Pharmacy Diabetes Self-Management Education program. Dr. Cornell’s current clinical practice is with the Access Community Health Network, where she trains, educates, and supervises students from the colleges of medicine, pharmacy, and health sciences as they provide diabetes education classes for patients in underserved community clinics. Dr. Cornell received her Bachelor of Science degree in pharmacy from the University of Illinois, College of Pharmacy in 1986 and her Doctor of Pharmacy degree from Midwestern University in 2002. Dr. Cornell recently completed her term as President of the Illinois Pharmacists Association in October 2011. She has received numerous awards and recognitions, including the 2010 Teacher of the Year Award, the 2010 American Association of Colleges of Pharmacy Student Engaged Community Service Award, and the 2005 Midwestern University Golden Apple Teaching Award. In 2008, she received fellow recognition from the American Association of Diabetes Educators (AADE) and the American Pharmacists Association. She is an active member of the ADA, as well as the AADE, where she served on the board of directors from 2004 to 2007. Dr. Cornell has served as an invited speaker nationally and internationally on diabetes and its related conditions and is recognized as a key opinion leader in the field of diabetes education. She has contributed to many peer-reviewed print and online publications in this field.

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The Next Generation: Exploring Current and Emerging Therapies for

Type 2 Diabetesyp

Susan Cornell, Pharm.D., CDE, FAPhA, FAADEAssistant Director of Pharmacy Practice and

Associate Professor of Pharmacy Practice

Midwestern University Chicago College of Pharmacy

Learning Objectives

• Discuss recent changes to national guidelines for the management of type 2 diabetes.

• Compare and contrast traditional and new diabetes pharmacotherapydiabetes pharmacotherapy.

• Describe emerging pharmacotherapy treatments for type 2 diabetes.

• Summarize current and emerging trends in diabetes care.

Treatment Guideline Comparison:

ADA/EASD vs. AACE

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WUZZLE #1

ADA 2012 Clinical Practice Recommendations:Summary of Revisions

New Recommendations

Initiate metformin (unless contraindicated) and lifestyle changes at time of diabetes diagnosis.

In newly diagnosed T2DM patients with markedly symptomatic /and/or elevated blood glucose levels or A1c, consider insulin

therapy, with or without additional agents, from the outset.

If non‐insulin monotherapy at maximal tolerated dose does not achieve or maintain the A1c target over 3‐6 months, add a second oral agent, a GLP‐1 receptor agonist, or insulin.

ADA. Diabetes Care. 2012; 35(suppl1):S11‐63.

T2DM = type 2 diabetes mellitusGLP‐1 = glucagon‐like peptide‐1

According to the revised ADA guidelines, which of the following oral agents are not considered part of the “two drug combination” therapy options?

1. ‐glucosidase inhibitors (AGI) 2 Di tid l tid 4 (DPP 4) i hibit ( li ti )2. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors (gliptins)

3. Dopamine agonists

4. Glinides

5. Sulfonylureas

6. Thiazolidinediones (TZDs or glitazones)

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Initial drug monotherapy

Efficacy ( HbA1c) Hypoglycemia Weight Side effects Costs

Healthy eating, weight control, increased physical activity

Metformin high low risk neutral/loss GI / lactic acidosis low

If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Efficacy ( HbA1c) Hypoglycemia Weight Major side effect(s) Costs

high low risk gain edema, HF, fx’s‡ high

Thiazolidine- dione

intermediate low risk neutral rare‡

high

DPP-4 Inhibitor

highest high risk gain hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

high low risk loss GI‡ high

GLP-1 receptor agonist

Sulfonylurea†

high moderate risk gain hypoglycemia‡ low


Sulfonylurea†

+

Thiazolidine-dione +

DPP-4 Inhibitor +

GLP-1 receptor agonist +

Insulin (usually basal) +

Metformin +

Metformin +

Metformin +

Metformin +

Metformin+

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:

Insulin# (multiple daily doses)

Three drug combinations

More complex insulin strategies

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

Inzucchi SE et al. Diabetes Care. 2012; 35:1364‐79.

American Association of Clinical Endocrinologists American College of Endocrinology (AACE/ACE) AlgorithmAlgorithm is stratified by A1c level

A1c ≤ 7.5%

– Start with monotherapy.If monotherapy fails, progress to dual and then to triple therapy. Finally, insulin therapy should be initiated, with or without additional agents.

A1c 7.6%–9.0%

– Begin dual therapy because no single agent is likely to achieve the A1c goal.If dual therapy fails, progress to triple therapy and then to insulin therapy, with or without additional orally administered agents.

A1c > 9.0%

– If the patient is asymptomatic, begin with triple therapy. If the patient is symptomatic, or therapy with similar medications has failed, initiate insulin therapy, either with or without additional orally administered agents.

Rodbard HW et al. Endocr Pract. 2009; 15:540‐59.

The Endocrine Society: Guideline Update

• Clinical Practice Guidelines on the Management of Hyperglycemia in Hospitalized Patients in a Non‐Critical Care Setting– All patients have blood glucose test upon hospital admission

• All patients with high glucose on admission receive POC blood glucose testing

– Glucose targets» Pre‐meal < 140 mg/dl» Random < 180 mg/dl

• Patients with diabetes should be treated with scheduled subcutaneous insulin regimen

www.endo‐society.org. URL in Reference List.

POC = point of care

See page 117 for enlarged view

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Case 1SL is newly diagnosed with T2DM x 2 months.A1c is 8.6%. BMI 32 kg/m2

Occupation: interstate truck driver. What should SL’s (target) A1c goal be?

1. < 6.5%

2. < 7.0 %

3. < 7.5%

4. < 8.0%

5. unsure

Case 2JC is a 79‐year‐old patient with T2DM x 22 years. A1c = 8.1% (x 4 years); BMI = 25 kg/m2; SCr = 1.1 mg/dLMetformin 1000 mg BIDGlimepiride 4 mg dailyJC resides in an assisted living apartment & has limited mobility. What should JC’s (target) A1c goal be?

1. < 6.5%

2. < 7.0 %

3. < 7.5%

4. < 8.0%

5. unsure

Setting Glucose Targets

Less Stringent (< 8%)

Less Stringent (< 8%)

More Stringent(as close to normal [6%] as possible)

More Stringent(as close to normal [6%] as possible)

(ADA < 7%; AACE ≤ 6.5%)

• Longer duration of diabetes• Limited life expectancy• Presence of complications/comorbidities• Greater concern about hypoglycemia

• Shorter duration of diabetes• Longer life expectancy• No significant CVD

Handelsman Y et al. Endocr Pract. 2011; 17(suppl 2):287‐302.

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Focus on Selection of Pharmacotherapy for T2DM

• Desired drug effects

– Protect remaining β‐cell function

Mi i i h l i i k– Minimize hypoglycemic risks

– Minimize weight gain

– Minimize adverse effects and drug interactions

– Cardiovascular benefit

Pharmacotherapy Options

Traditional Commonly used

Traditional Not commonly used

Newer Commonly used

NewerNot commonly used

Biguanides ‐glucosidase inhibitors (AGI)

Dipeptidylpeptidase‐4 (DPP‐4) inhibitors

Dopamine agonists

Sulfonylureas Glinides Glucagon‐like peptide‐1 (GLP‐1)

Amylinomimeticpeptide 1 (GLP 1) agonists

Thiazolidinediones Bile acidsequestrant

Insulin

Weight Effect

Hypoglycemiaβ‐cell

protectionCVD

benefitsCost

Other Considerations

‐glucosidase inhibitors (AGI)

neutral low risk possible possible $ to $$GI adverse effects (gas),

dose frequency

Amylinomimetic loss low risk possible yes $$GI adverse effects (nausea), injectable,

dose frequency

Bile acidsequestrant

neutral or loss

low risk possible yes $$GI adverse effects (constipation),

dose frequency

Biguanides loss low risk possible yes $GI adverse effects (diarrhea), renal and

hepatic impairment monitoring

DPP‐4 Inhibitors (gliptins)

neutral low risk possible yes $$$ minimal adverse effects(g )

Dopamine agonist

neutral or loss

low risk unknown yes/no $$$GI adverse effects (nausea) ,

hypotension, dizziness

GLP-1 agonists loss low risk possible yes $$$ GI adverse effects (nausea), injectable

Insulin gain or

loss

risk – bolus

low risk ‐ basalpossible possible $ to $$

injectable, dose frequency (bolus), increased SMBG

Secretagogues Sulfonylureas &

glinidesgain risk no no

$ to $$immediate short‐term response,

increased SMBG,

dose frequency (glinides)

TZD’s (glitazones) gain low risk possible yes/no $$

4‐8 weeks for response, redistribution of subcutaneous/visceral fat,

edema, bone loss, fracture, bladder cancer


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Glucose Lowering Comparison Monotherapy Route of

Administration Target glucose: FPG or PPG

A1c (%) Reduction

Sulfonylurea Oral Both 1.5-2.0

Metformin Oral FPG 1.5

Glitazones Oral Both 1.0-1.5

Meglitinides Oral PPG 0.5-2.0

-Glucosidase Inhibitors

Oral PPG 0.5-1.0

Adapted from Unger J et al. Postgrad Med. 2010; 122:145‐57.

Cornell S et al. Postgrad Med. 2012; 124:84‐94.

DDP-4 Inhibitors Oral PPG 0.5-0.7

Bile Acid Sequestrant Oral PPG 0.4

Dopamine agonists Oral PPG 0.4

GLP-1 agonists Injectable Short acting ‐ PPGLong‐acting ‐ both

0.8-1.5

Amylin analogs Injectable PPG 0.6

Insulin Injectable Basal ‐ FPGBolus ‐ PPG

Open to target

Newer Therapies

GLP-1 Agonists

DrugExpectedDecreasein A1c (%)

Exenatide BID 10 mcg bid 0.8-0.9

DPP-4 Inhibitors

Drug(Monotherapy)

ExpectedDecreasein A1c (%)

Sitagliptin 100 mg 0.6

GLP‐1 Agonists and DPP‐4 Inhibitors

Drucker DJ et al. Lancet. 2008; 372(9645):1240‐50.Blonde L et al. Diabetes Obes Metab. 2009; 11(suppl 3):26‐34.Ahren B. Best Pract Res Clin Endocrinol Metab. 2007; 21:517‐33.Buse JB et al. The Duration‐1 Study Group. Diabetes Care. 2010; 33:1255‐61.Gomis R et al. Diabetes Obes Metab. 2011; 13:653‐61.

* Not FDA-approved

g

Liraglutide 1.8 mg daily 1-1.5

Exenatide QW2 mg weekly 1.8-2.1

Saxagliptin 0.73

Linagliptin 0.51

Alogliptin* 0.6


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Pharmacologic and Pharmacokinetic Differences among GLP‐1 Agonists

Agent Description Tmax, t1/2

Active Metabolites, Significant Interactions Elimination

Exenatide BID Synthetic analog of extendin‐4 found in saliva of Heloderma suspectum (lizard); 53% homology to native GLP‐1

2.1 h2.4 h

None Mainly renal; not recommended for patients with ESRD or severe renal impairment

Liraglutide Acylated analog of human GLP‐1; 97% homology to native GLP‐1

8–12 h13 h

None Mainly metabolized by proteolytic degradation; 97 gy 3 p y g ;use caution in patients with renal impairment

Exenatide QW Exenatide suspended in PLG microspheres

2–5 wkNR

None Renal

Albiglutide GLP‐1 dimer genetically fused to human albumin

3–5 d6–7 d

NR NR

Dulaglutide GLP‐1 IgG4‐Fc fusion protein ~70 h~4 d

NR NR

Lixisenatide Extendin‐4‐like GLP‐1 agonist modified C‐terminally

~2 h~3 h

NR Renal

Byetta PI; Sept 2010. Victoza PI; Dec 2010. Gilbert MP, Pratley RE. Am J Med. 2009; 122(suppl 6):S11–S24.Bischoff LA et al. Expert Opin Pharmacother. 2011; 12:1297–1303. St Onge EL, Miller SA. Expert Opin Biol Ther. 2010; 10:801–6.Umpierrez GE et al. Diabetes Obes Metab. 2011; 13:418–25. Christensen M et al. Expert Opin Investig Drugs. 2011;20:549–57.

Approved and Standard Investigational Doses for GLP‐1 Agonists

AgentInitial Dose (Duration) Regular Dose Dose Frequency and Timing

Exenatide BID 5 µg (1 month) 5 µg or10 µg

Twice daily; given within 60‐minute period before morning and evening meals

Liraglutide 0.6 mg (1 week)

1.2 mg or1.8 mg

Once daily; any time of day

Exenatide QW 2 mg 2 mg Once weekly; timing not specified

Albiglutide 30 mg 30 mg Once weekly; timing not specified

Dulaglutide NR 0.75 mg or1.5 mg

Once weekly; timing not specified

Lixisenatide 10 µg (2 weeks)

20 µg Once daily; within 60 min before breakfast.

Byetta PI; Sept 2010. Victoza PI; Dec 2010.Bischoff LA et al. Expert Opin Pharmacother. 2011; 12:1297–1303.ClinicalTrials.gov. NCT01126580 (dulaglutide). URL in Ref List.ClinicalTrials.gov. NCT01169779 (lixisenatide). URL in Ref List.

Pharmacologic and Pharmacokinetic Characteristics of DPP‐4 Inhibitors

Agent

Ex Vivo DPP‐4 Inhibition, %

Metabolism EliminationMaximum24 h

Postdose

Linagliptin ~80% ~70 ~90% eliminated unchanged; exposure decreased by CYP3A4 or P gp inducers

Biliary (>70% unchanged as parent), <6% via kidney

P‐gp inducers

Saxagliptin ~80% ~70 Hepatically metabolized to active metabolite via CYP3A4/5

Renal (12%‐29% as parent, 21%‐52% as metabolite)

Sitagliptin ~97% ~80 Not appreciably metabolized

Renal (>80% unchanged as parent)

Alogliptin ~90% ~75 Not appreciably metabolized


Deacon CF. Diabetes Obes Metab. 2011; 13:7–18. Tradjenta PI; May 2011. Onglyza PI; Feb 2011. Januvia PI; Apr 2011.




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Approved and Standard Investigational Doses of DPP‐4 Inhibitors

All DPP‐4 inhibitors should be taken orally, once daily, with or without food Dose titration at the beginning of therapy is not required

Agent Standard Dose

Moderate Renal

Impairment

Severe Renal Impairment or

ESRD OtherAgent Standard Dose Impairment ESRD Other

Linagliptin 5 mg 5 mg 5 mg None

Saxagliptin 2.5, 5 mg 2.5 mg 2.5 mg 2.5 mg with strong CYP3A4/5 inhibitors

Sitagliptin 100 mg 50 mg 25 mg None

Alogliptin 12.5, 25 mg ND ND ND

Tradjenta PI; May 2011. Onglyza PI; Feb 2011. Januvia PI; Apr 2011. Andukuri A et al. Diabetes Metab Syndr Obes. 2009; 2:117–26.

Dopamine Agonists (bromocriptine)

• ↑ dopamine in the brain to change circadian neuro‐endocrine rhythms (similar to that in hibernation)

– Body fat ‐ Possibly due to ↓ TG from diet

– ↓ liver glucose output ‐ Possibly from over‐production of cortisol in T2DM

– Best used in pre‐diabetes or early disease due to ↑ insulin resistance; though, potentially beneficial throughout duration of disease.

• Lowers postprandial glucosep p g

• Decreases A1c by 0.4% (~10‐15 mg/dl)

• Most common adverse effects

• Nausea, vomiting

• Headache

• Fatigue

• Hypotension

• ↓ TGScranton RE et al. BMC Endocr Disord. 2007; 7:3.

Amylinomimetic Agents (pramlintide)• Mimics amylin action of the pancreas and (brain)

– Enhances appropriate insulin and amylin secretion from the pancreas

• Results in brain satiety

– Delays gastric emptying time

• Can be used throughout duration of disease– Adjunct to insulin therapy

• Lowers postprandial glucoseD A1 b 0 6% ( 15 20 /dl t di l)Decreases A1c by 0.6% (~15‐20 mg/dl; more postprandial)

• Most common adverse effects– Weight loss

– Stomach upset

– Headache

• Caution in patients on insulin and/or drugs that alter GI motility– May need to ↓ insulin dose

– May need to reschedule dose of other drugs


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Wuzzle #2

Rational Choices for Oral Agent Combinations

• Drugs that target different metabolic defects

• Drugs that target fasting and postprandial glucose control

Possible Combination Therapies

< 1.0% A1c lowering needed◦ Postprandial needs coverage, as well as fasting Biguanide + TZD Biguanide + DPP‐4 inhibitor Biguanide + GLP‐1 agonist (short acting)

1 2% A1c lowering needed 1‐2% A1c lowering needed◦ Postprandial needs coverage, as well as fasting Biguanide + TZD Biguanide + GLP‐1 agonist (short or long acting) Biguanide + TZD + GLP‐1 agonist (short or long acting) Biguanide + TZD + DPP‐4 inhibitor

◦ Note: Basal insulin can be added to any of the above combinations if needed.

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Possible Combination Therapies

• > 2.0% A1c lowering needed

– Need to fix fasting first, as well as consider postprandial

• Biguanide + DPP‐4 inhibitor + basal insulin

• Biguanide + GLP‐1 agonist (short acting or long acting) + basal insulin

• Biguanide + TZD + basal insulin

• Basal + bolus insulin

• Biguanide + basal insulin + bolus insulin

Post‐prandial Glucose Elevation Intervention

In the Pipeline…………….

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Some Agents in the Pipeline

• Sodium glucose cotransporter (SGLT‐2) inhibitors

• Ultra‐long‐acting insulin

• Insulin & GLP‐1 agonist combination

• GPR119 agonists• GPR119 agonists

• Free fatty acid receptor‐1 (FFAR‐1) agonist

SGLT‐2

• SGLT‐2 (only)

– Dapagliflozin

– Canagliflozin

– Empagliflozin

I lifl i– Ipragliflozin

– Luseogliflozin

– Tofogliflozin

– Ertugliflozin

• SGLT‐2/SGLT‐1 inhibitor

– LX4211

SGLT‐2

• Patient eats and food is broken down into glucose and other things

• Kidneys allow glucose molecules to pass from the bloodstream into the glomerulus

– But the glucose is subsequently reabsorbed via active transport mechanisms in the proximal convoluted tubule rather than being lost with the urine

• Two sodium‐glucose co‐transporters have been identified that cause the glucose to be reabsorbed: SGLT‐1 and SGLT‐2

– SGLT‐2, which is found only in the proximal tubule of the kidney, accounts for most of the re‐absorption of glucose

– SGLT‐1, which is also found in the gut and other tissues, accounts for only about 10% of glucose re‐absorption

List JF et al. Diabetes Care. 2009; 32:650‐7.Wilding JP et al. Diabetes Care. 2009: 32:1656‐62.

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SGLT‐2 Inhibitors

• Work in kidney to decrease reabsorption of glucose

◦ Total glucose/day not reabsorbed: 50‐80 grams

• Metabolic effects

◦ FPG reduced 15‐20mg/dl

◦ A1c reduced 0.5 to 0.7% (placebo subtracted)◦ Body weight reduced 2‐3 kg in 12 weeks

◦ Systolic BP reduced 3‐5 mmHg


SGLT‐2 InhibitorsAdverse Effects• Adverse effects include both constipation and diarrhea, nausea, and reports of hypoglycemia

• Some women have developed vaginal infections

• Some important blood constituents were altered– Increased serum magnesium, serum phosphate, hematocrit

o Possibly due to diuresis

– Deceased uric acid

• In clinical studies, more GI problems seen, especially in patients taking metformin in combination with a SGLT‐2 inhibitor


Insulin

• Ultra‐long‐acting Insulin

– Degludec

– Degludec Plus

• Insulin & GLP‐1 combination

– Degludec + Liraglutide

– Glargine + Lixisenatide

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Ultra‐long‐acting Insulin

Degludec (IDeg)– Clinical trial reports (BEGIN)

– Once daily dosing o A1c ↓ 1.1% in IDeg (noninferior to insulin glargine)

– A1c ↓ 1.3% in IDeg‐200o Less hypoglycemic eventso Less weight gain26+ hours coverageo 26+ hours coverage

– IDeg (100 U/mL)– IDeg‐200 (200 U/mL)

o For patients on large basal insulin doses– e.g., > 80 units daily

King A. J Fam Pract. 2012; 61(5 suppl):S28‐31.Bergenstal R. AACE 21st Annual Scientific and Clinical Congress. May 27, 2012.

Basal Insulin Profiles

n Levels NPH (10–20 hr)

D i ( 24 h )

Degludec (> 26 hr)

Rosenstock J. Clin Cornerstone. 2001;4(2):50‐64.King A. J Fam Pract. 2012.61(5 suppl):S28‐31.

0 2 4 6 8 10 12 14 16 18 20 22 24

Plasm

a Insuli

Time (hours)

Glargine (< 24 hr)

Detemir (< 24 hr)

Basal Insulin DegludecFlat, Stable Profile of Both 100 Unit/ml

and 200 Unit/ml Formulations

GIR: Glucose infusion rateHeise et al. ADA 2012, Oral 349 Abstract (Trial: NN1250‐1987). Nosek et al. IDF 2011: P‐1452; Diabetologia 2011; 54(suppl. 1):S429 (1055‐P); Diabetes 2011;60(suppl. 1A):LB14.

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Degludec Plus

Degludec Plus

– Basal degludec + bolus boost of aspart

– Clinical trial reports (BOOST)

Once daily dosing Once daily dosing – Degludec + aspart prior to eveningmeal– A1c ↓ up to 1.1%

– Less hypoglycemic events

– Less weight gain

– Sustained basal coverage (~26 hours)

ClinicalTrials.gov. NCT01513590. URL in Ref List.Hirsch IB et al. Diabetes Care. 2012 Nov; 35(11): 2174‐81.

Basal Insulin – GLP‐1 agonist combination

• Degludec + liraglutide– Study NCT01336023

• Expected to be completed Nov 2012

• Fixed dose combination– Subcutaneous once dailySubcutaneous, once daily

• Benefits of combination therapy– Low hypoglycemia risk

– Weight reduction

– BP reduction

– Improved lipid profile

Baruah MP, Kalra S. Recent Pat Endocr Metab Immune Drug Discov. 2012. 6:129‐35.

Other Pipeline Agents

• GPR119 agonists

– Receptor in the pancreas (β‐cells) and GI tract

– Stimulation with synthetic ligands results in increased release of insulin, GLP‐1, and GIP

I i t l GLP 1 d GIP i T2DM• Increase in post‐meal GLP‐1 and GIP in T2DM

• Not associated with hypoglycemia

Overton HA. Br J Pharmacol. 2008; 153(suppl 1):S76‐81.Katz LB. Diabetes Obes Metab. 2012; 14:709‐16.

GIP = gastric insulinotropic peptide

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Other Pipeline Agents

• Free Fatty Acid Receptor‐1 (FFAR‐1)

– A.K.A. GPR40

• Expressed in pancreatic β‐cells

• Activation of this receptor results in fatty acid–induced l ti l t d i li tiglucose‐stimulated insulin secretion

• In a phase 2, 12‐week clinical trial, the FFAR‐1 activator TAK‐875 significantly reduced A1c, compared with placebo with no increase in hypoglycemia.

Kebede MA. Diabetes Obes Metab. 2009; 11(suppl 4):10‐20.Burant CF. Lancet. 2012; 379(9824):1403‐11.

Key Points of Discussion at the 2012 ADA Scientific Sessions

• Minimize hypoglycemia

• Early detection and treatment for prediabetes

– Metformin + lifestyley

– TZD + GLP‐1 agonist + lifestyle

• β‐cell function can be preserved for 3.5 years after diagnosis of T2DM

– Combination therapyo Complementary mechanisms


• TODAY study

– Maintaining glycemic control in youth with T2DM• Metformin + lifestyle

• Metformin + TZD

• ORIGIN study

– Outcomes reduction with initial glargine intervention• Early basal insulin use in prediabetes and T2DM to evaluate

– Cardiovascular disease

– Cancer

– Hypoglycemia

– Weight gain

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WUZZLE #3


• 3 types of adipose tissue– White (bad)– Brown (good)– Beige (adipose tissue precursor)

• Brown fat is decreased in obesityBrown fat is decreased in obesity– Bariatric surgery increases brown adipose tissue (BAT) activity

• ↑ brown fat

• So how do we “brown” our white/beige fat?– Cold temps– Sympathetic activity– Coffee, green tea– Exercise

Take Home Message

• Diabetes management is constantly evolving– Clinicians must stay current with new therapies and trends

• The longer we wait – the more damage is done!– Earlier diagnosis and treatment needed– Appropriate drug therapy + lifestyle modification◦ Monotherapy rarely works and only for short term

• Newer and emerging therapies target key organ defects

• Individualize glycemic goals and therapy– One size does NOT fit all – Key considerations in therapy◦ Save the β‐cell◦ Minimize hypoglycemia ◦ Minimize weight gain

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What questions can I answer for you?

[email protected]

116

Initial drug monotherapy

Efficacy ( HbA1c) Hypoglycemia Weight Side effects Costs

Healthy eating, weight control, increased physical activity

Metformin high low risk neutral/loss GI / lactic acidosis low


Metformin Metformin Metformin Metformin MetforminMetformin+

Metformin+

Metformin+

Metformin +

Metformin+

Efficacy ( HbA1c) Hypoglycemia Weight Major side effect(s) Costs

high low risk gain edema, HF, fx’s‡ high

Thiazolidine- dione

intermediate low risk neutral rare‡

high

DPP-4 Inhibitor

highest high risk gain hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

high low risk loss GI‡ high

GLP-1 receptor agonist

Sulfonylurea†

high moderate risk gain hypoglycemia‡ low


Sulfonylurea†

+

Thiazolidine-dione +

DPP-4 Inhibitor +

GLP-1 receptor agonist +

Insulin (usually basal) +

Metformin+

Metformin+

Metformin+

Metformin +

Metformin+

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§

Three drug combinations

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:

Insulin# (multiple daily doses)

More complex insulin strategies

Inzucchi SE et al. Diabetes Care. 2012; 35:1364‐79.

117

Weight Effect

Hypoglycemiaβ‐cell

protectionCVD

benefitsCost

Other Considerations

‐glucosidase inhibitors (AGI)

neutral low risk possible possible $ to $$GI adverse effects (gas),

dose frequency

Amylinomimetic loss low risk possible yes $$GI adverse effects (nausea), injectable,

dose frequencyq y

Bile acidsequestrant

neutral or loss

low risk possible yes $$GI adverse effects (constipation),

dose frequency

Biguanides loss low risk possible yes $GI adverse effects (diarrhea), renal and

hepatic impairment monitoring

DPP‐4 Inhibitors (gliptins)

neutral low risk possible yes $$$ minimal adverse effectsg

Dopamine agonist

neutral or loss

low risk unknown yes/no $$$GI adverse effects (nausea) ,

hypotension, dizziness

GLP-1 agonists loss low risk possible yes $$$ GI adverse effects (nausea), injectable

Insulin gain or

loss

risk – bolus

low risk ‐ basalpossible possible $ to $$

injectable, dose frequency (bolus), increased SMBG

Secretagogues Sulfonylureas &

glinides

gain risk no no$ to $$

immediate short‐term response, increased SMBG,

dose frequency (glinides)

TZD’s (glitazones) gain low risk possible yes/no $$

4‐8 weeks for response, redistribution of subcutaneous/visceral fat,

edema, bone loss, fracture, bladder cancer

118

Glucose Lowering Comparison Monotherapy Route of

Administration Target glucose: FPG or PPG

A1c (%) Reduction

Sulfonylurea Oral Both 1.5-2.0

Metformin Oral FPG 1.5

Glitazones Oral Both 1.0-1.5

Meglitinides Oral PPG 0.5-2.0

-Glucosidase Inhibitors

Oral PPG 0.5-1.0

DDP-4 Inhibitors Oral PPG 0.5-0.7

Bile Acid Sequestrant Oral PPG 0.4

Dopamine agonists Oral PPG 0.4

GLP-1 agonists Injectable Short acting ‐ PPGLong‐acting ‐ both

0.8-1.5

Adapted from Unger J et al. Postgrad Med. 2010; 122:145‐57.

Cornell S et al. Postgrad Med. 2012; 124:84‐94.

Long acting both

Amylin analogs Injectable PPG 0.6

Insulin Injectable Basal ‐ FPGBolus ‐ PPG

Open to target

119

Pharmacologic and Pharmacokinetic Differences among GLP‐1 Agonists

Agent Description Tmax, t1/2

Active Metabolites, Significant Interactions Elimination

Exenatide BID Synthetic analog of extendin‐4 2.1 h None Mainly renal; not y g 4found in saliva of Heloderma suspectum (lizard); 53% homology to native GLP‐1

2.4 hy ;

recommended for patients with ESRD or severe renal impairment

Liraglutide Acylated analog of human GLP‐1; 97% homology to native GLP‐1

8–12 h13 h

None Mainly metabolized by proteolytic degradation; use caution in patients with renal impairment

Exenatide QW Exenatide suspended in PLG microspheres

2–5 wkNR

None Renal

Albigl tid GLP di g ti ll f d t d NR NRAlbiglutide GLP‐1 dimer genetically fused to human albumin

3–5 d6–7 d

NR NR

Dulaglutide GLP‐1 IgG4‐Fc fusion protein ~70 h~4 d

NR NR

Lixisenatide Extendin‐4‐like GLP‐1 agonist modified C‐terminally

~2 h~3 h

NR Renal

Byetta PI; Sept 2010. Victoza PI; Dec 2010. Gilbert MP, Pratley RE. Am J Med. 2009; 122(suppl 6):S11–S24.Bischoff LA et al. Expert Opin Pharmacother. 2011; 12:1297–1303. St Onge EL, Miller SA. Expert Opin Biol Ther. 2010; 10:801–6.Umpierrez GE et al. Diabetes Obes Metab. 2011; 13:418–25. Christensen M et al. Expert Opin Investig Drugs. 2011;20:549–57.

Approved and Standard Investigational Doses for GLP‐1 Agonists

AgentInitial Dose (Duration) Regular Dose Dose Frequency and Timing

Exenatide BID 5 µg (1 month) 5 µg or10 µg

Twice daily; given within 60‐minute period before morning and evening meals

Liraglutide 0.6 mg (1 week)

1.2 mg or1.8 mg

Once daily; any time of day

Exenatide QW 2 mg 2 mg Once weekly; timing not specified

Albiglutide 30 mg 30 mg Once weekly; timing not specified

Dulaglutide NR 0.75 mg or Once weekly; timing not specified1.5 mg

Lixisenatide 10 µg (2 weeks)

20 µg Once daily; within 60 min before breakfast.

Byetta PI; Sept 2010. Victoza PI; Dec 2010.Bischoff LA et al. Expert Opin Pharmacother. 2011; 12:1297–1303.ClinicalTrials.gov. NCT01126580 (dulaglutide). URL in Ref List.ClinicalTrials.gov. NCT01169779 (lixisenatide). URL in Ref List.

120

Pharmacologic and Pharmacokinetic Characteristics of DPP‐4 Inhibitors

Ex Vivo DPP‐4 Inhibition, %

24 h Agent Metabolism EliminationMaximum Postdose

Linagliptin ~80% ~70 ~90% eliminated unchanged; exposure decreased by CYP3A4 or P‐gp inducers

Biliary (>70% unchanged as parent), <6% via kidney

Saxagliptin ~80% ~70 Hepatically metabolized to active metabolite via CYP3A4/5

Renal (12%‐29% as parent, 21%‐52% as metabolite)

/

Sitagliptin ~97% ~80 Not appreciably metabolized


Alogliptin ~90% ~75 Not appreciably metabolized


Deacon CF. Diabetes Obes Metab. 2011; 13:7–18. Tradjenta PI; May 2011. Onglyza PI; Feb 2011. Januvia PI; Apr 2011.

Approved and Standard Investigational Doses of DPP‐4 Inhibitors

All DPP‐4 inhibitors should be taken orally, once daily, with or without food Dose titration at the beginning of therapy is not required

Agent Standard Dose

Moderate Renal

Impairment

Severe Renal Impairment or

ESRD Other

Linagliptin 5 mg 5 mg 5 mg None

Saxagliptin 2.5, 5 mg 2.5 mg 2.5 mg 2.5 mg with strong CYP3A4/5 3 4/5inhibitors

Sitagliptin 100 mg 50 mg 25 mg None

Alogliptin 12.5, 25 mg ND ND ND

Tradjenta PI; May 2011. Onglyza PI; Feb 2011. Januvia PI; Apr 2011. Andukuri A et al. Diabetes Metab Syndr Obes. 2009; 2:117–26.

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S E L E C T E D R E F E R E N C E S A N D R E S O U R C E S

Ahren B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab. 2007; 21:517-33. American Diabetes Association. Standards of medical care in diabetes‐‐2012. Diabetes Care. 2012; 35(suppl 1):S11‐63. Available at: http://care.diabetesjournals.org/content/35/Supplement_1/S11.full.pdf+html. Andukuri R, Drincic A, Rendell M. Alogliptin: a new addition to the class of DPP-4 inhibitors. Diabetes Metab Syndr Obes. 2009; 2:117-26. Baruah MP, Kalra S. The novel use of GLP-1 analogue and insulin combination in type 2 diabetes mellitus. Recent patents on endocrine, metabolic & immune drug discovery. Recent Pat Endocr Metab Immune Drug Discov. 2012; 6:129-35. Bergenstal R. 200 U/mL insulin degludec improves glycemic control similar to insulin glargine with a low risk of hypoglycemia in insulin-naïve people with type 2 diabetes. Presented at the American Association of Clinical Endocrinologists 21st Annual Scientific and Clinical Congress. Philadelphia, PA: May 27, 2012. Bischoff LA, Jabbour SA, Miller JL. Exenatide once weekly in type 2 diabetes mellitus. Expert Opin Pharmacother. 2011; 12:1297-1303. Blonde L, Russell-Jones D. The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1-5 studies. Diabetes Obes Metab. 2009; 11(suppl 3):26-34. Burant CF. TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2012; 379:1403-11. Buse JB, Drucker DJ, Taylor KL et al. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010; 33:1255-61. Christensen M, Knop FK, Vilsboll T et al. Lixisenatide for type 2 diabetes mellitus. Expert Opin Investig Drugs. 2011; 20:549-57. ClinicalTrials.gov. A study of LY2189265 compared to sitagliptin in patients with type 2 diabetes mellitus on metformin. NCT01126580 (dulaglutide). Available at: http://clinicaltrials.gov/ct2/show?term=LY2189265+AND+phase+3&rank=2. ClinicalTrials.gov. A trial comparing efficacy and safety of insulin degludec/insulin aspart and BIAsp 30 in insulin naïve subjects with type 2 diabetes (BOOST™). NCT01513590. Available at: http://clinicaltrials.gov/ct2/show/NCT01513590. ClinicalTrials.gov. Efficacy and safety of lixisenatide in patients with type 2 diabetes mellitus insufficiently controlled by metformin (GetGoal-M-As). NCT01169779 (lixisenatide). Available at: http://clinicaltrials.gov/ct2/show?term=lixisenatide&rank=2. Cornell S, Dorsey VJ. Diabetes pharmacotherapy in 2012: considerations in medication selection. Postgrad Med. 2012; 124:84-94.

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Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab. 2011; 13:7-18. Drucker DJ, Buse JB, Taylor K et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008; 372:1240-50. Gilbert MP, Pratley RE. Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus. Am J Med. 2009; 122(6 suppl):S11-24. Gomis R, Espadero RM, Jones R et al. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011; 13:653-61. Handelsman Y, Mechanick JI, Blonde L et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan: executive summary. Endocr Pract. 2011; 17(suppl 2):287-302. Available at: https://www.aace.com/sites/default/files/DMGuidelinesCCP.pdf. Hirsch IB, Bode B, Courreges JP et al. Insulin Degludec/Insulin Aspart Administered Once Daily at Any Meal, With Insulin Aspart at Other Meals Versus a Standard Basal-Bolus Regimen in Patients With Type 1 Diabetes: A 26-week, phase 3, randomized, open-label, treat-to-target trial. Diabetes Care. 2012; 35:2174-81. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012; 35:1364-79. Available at: http://care.diabetesjournals.org/content/early/2012/04/17/dc12-0413.full.pdf+html. Katz LB. Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes. Diabetes Obes Metab. 2012; 14:709-16. Kebede MA. Lipid receptors and islet function: therapeutic implications? Diabetes Obes Metab. 2009; 11(suppl 4):10-20. King A. Advances in insulin therapy: a review of insulin degludec. J Fam Pract. 2012; 61(5 suppl):S28-31. List JF, Woo V, Morales E et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009; 32:650-7. Overton HA. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br J Pharmacol. 2008; 153(suppl 1):S76-81. Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009; 15:540‐59.

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Rosenstock J. Insulin therapy: optimizing control in type 1 and type 2 diabetes. Clin Cornerstone. 2001; 4(2):50-64. Scranton RE, Gaziano JM, Rutty D et al. A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset or placebo. BMC Endocr Disord. 2007; 7:3. St Onge EL, Miller SA. Albiglutide: a new GLP-1 analog for the treatment of type 2 diabetes. Expert Opin Biol Ther. 2010; 10:801-6. The Endocrine Society. Management of hyperglycemia in hospitalized patients in non-critical care setting: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012; 97:16-38. Available at: http://www.endo-society.org/guidelines/upload/FINAL-Standalone-Management-of-Hyperglycemia-Guideline.pdf. Umpierrez GE, Blevins T, Rosenstock J et al. The effects of LY2189265, a long-acting glucagon-like peptide-1 analogue, in a randomized, placebo-controlled, double-blind study of overweight/obese patients with type 2 diabetes: the EGO study. Diabetes Obes Metab. 2011; 13:418-25. Unger J, Parkin CG. Type 2 diabetes: an expanded view of pathophysiology and therapy. Postgrad Med. 2010; 122:145-57. Wilding JP, Norwood P, T’joen C et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009; 32:1656-62.

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S E L F – A S S E S S M E N T C R O S S W O R D P U Z Z L E

Across: Down: 3 ‐ Generic name for newly approved long‐acting

insulin 5 ‐ The good fat 6 ‐ Drug with the best A1c lowering potential 7 ‐ Popular incretin hormone 9 ‐ Critical undesirable drug side effect

1 ‐ A new class of drugs that decreases renal absorption of glucose

2 ‐ Oral agent with most hypoglycemic risk 4 ‐ The best pharmacotherapy approach 8 ‐ Hormone that affects neuro‐endocrine

rhythm 9 ‐ The pre‐meal blood glucose goal is 140‐

180 mg/dL for patients in this setting

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The Next Generation: Exploring Current and Emerging ... · guidelines and evolving pharmacotherapy to optimize management of type 2 diabetes. ... Summarize current and emerging trends