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

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

AGENDA 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

FACULTY 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

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

DISCLOSURE STATEMENT 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.

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

ACTIVITY OVERVIEW 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.

ACTIVITY OBJECTIVES 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.

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

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

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.

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

Susan Cornell, Pharm.D., CDE, FAPhA, FAADE Assistant 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 pharmacotherapy. • Describe emerging pharmacotherapy treatments for type 2 diabetes. • Summarize current and emerging trends in diabetes care.

Treatment Guideline Comparison:

ADA/EASD vs. AACE

100 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.

T2DM = type 2 diabetes mellitus GLP‐1 = glucagon‐like peptide‐1

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

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. Dipep tidy l peptidase‐4 (DPP‐4) in hibitors (liti)(gliptins) 3. Dopamine agonists 4. Glinides 5. Sulfonylureas 6. Thiazolidinediones (TZDs or glitazones)

101 Healthy eating, weight control, increased physical activity Initial drug monotherapy Metformin See page 117 for enlarged view Efficacy ( HbA1c) high Hypoglycemia low risk Weight neutral/loss Side effects GI / lactic acidosis Costs 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 + + + + + Two drug Sulfonylurea† Thiazolidine- DPP-4 GLP-1 receptor Insulin (usually combinations* dione Inhibitor agonist basal)

Efficacy ( HbA1c) high high intermediate high highest Hypoglycemia moderate risk low risk low risk low risk high risk Weight gain gain neutral loss gain ‡ ‡ ‡ ‡ ‡ Major side effect(s) hypoglycemia edema, HF, fx’s rare GI hypoglycemia Costs low high high high variable

If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference): Metformin Metformin Metformin Metformin Metformin + + + + + Three drug Sulfonylurea† Thiazolidine- DPP-4 GLP-1 receptor Insulin (usually combinations dione Inhibitor agonist basal) + + + + + TZD SU† SU† SU† TZD

or DPP-4-i or DPP-4-i or TZD or TZD or DPP-4-i

or GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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:

More complex # insulin strategies Insulin (multiple daily doses) Inzucchi SE et al. Diabetes Care. 2012; 35:1364‐79.

American Association of Clinical Endocrinologists American College of Endocrinology (AACE/ACE) Algorithm Algorithm 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

POC = point of care

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

102 Case 1 SL 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 2 JC 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/dL Metformin 1000 mg BID Glimepiride 4 mg daily JC 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 (ADA < 7%; More Stringent AACE ≤ 6.5%) (as close to normal (< 8%) [6%] as possible)

• Longer duration of diabetes • Shorter duration of diabetes • Limited life expectancy • Longer life expectancy • Presence of complications/comorbidities • No significant CVD • Greater concern about hypoglycemia

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

103 Focus on Selection of Pharmacotherapy for T2DM

• Desired drug effects

– Protect remaining β‐cell function

– Min im ize hhlypoglycem ic rikisks

– Minimize weight gain

– Minimize adverse effects and drug interactions

– Cardiovascular benefit

Pharmacotherapy Options

Traditional Traditional Newer Newer Commonly used Not commonly used Commonly used Not commonly used Biguanides ‐glucosidase Dipeptidyl Dopamine agonists inhibitors (AGI) peptidase‐4 (DPP‐4) inhibitors Sulfonylureas Glinides Glucagon‐like Amylinomimetic peptide‐1 (GLP‐1) agonists

Thiazolidinediones Bile acid sequestrant Insulin

Weight β‐cell CVD Other Considerations Hypoglycemia Cost Effect protection benefits See page 118 for enlarged view ‐glucosidase GI adverse effects (gas), neutral low risk possible possible $ to $$ inhibitors (AGI) dose frequency

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

Bile acid neutral GI adverse effects (constipation), low risk possible yes $$ sequestrant or loss dose frequency GI adverse effects (diarrhea), renal and Biguanides loss low risk possible yes $ hepatic impairment monitoring DPP‐4 Inhibitors neutral low risk possible yes $$$ minimal adverse effects (gliptins )

Dopamine neutral GI adverse effects (nausea) , low risk unknown yes/no $$$ agonist or loss hypotension, dizziness

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

Insulin gain or risk –bolus injectable, dose frequency (bolus), possible possible $ to $$ loss low risk ‐ basal increased SMBG Secretagogues immediate short‐term response, $ to $$ Sulfonylureas & gain risk no no increased SMBG, glinides dose frequency (glinides)

TZD’s 4‐8 weeks for response, redistribution of subcutaneous/visceral fat, (glitazones) gain low risk possible yes/no $$ edema, bone loss, fracture, bladder cancer

104 Glucose Lowering Comparison See page 119 for enlarged view Monotherapy Route of Target glucose: A1c (%) Administration FPG or PPG 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 Oral PPG 0.5-1.0 Inhibitors 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 ‐ PPG 0.8-1.5 Long‐acting ‐ both Amylin analogs Injectable PPG 0.6 Insulin Injectable Basal ‐ FPG Open to target Bolus ‐ PPG Adapted from Unger J et al. Postgrad Med. 2010; 122:145‐57. Cornell S et al. Postgrad Med. 2012; 124:84‐94.

Newer Therapies

GLP‐1 Agonists and DPP‐4 Inhibitors

GLP-1 Agonists DPP-4 Inhibitors Expected Expected Drug Drug Decrease Decrease (Monotherapy) in A1c (%) in A1c (%)

Exenatide BID Sitagliptin 100 mg 0.6 0.8-0.9 10 mcg bid Saxagliptin 0.73 Liraglutide 1-1.5 1.8 mg daily Linagliptin 0.51 Exenatide QW 1.8-2.1 2 mg weekly Alogliptin* 0.6

* Not FDA-approved

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.

105 Pharmacologic and Pharmacokinetic Differences See page 120 for enlarged view among GLP‐1 Agonists

Active Metabolites, Significant

Agent Description Tmax, t1/2 Interactions Elimination Exenatide BID Synthetic analog of extendin‐4 2.1 h None Mainly renal; not found in saliva of Heloderma 2.4 h recommended for suspectum (lizard); 53% homology patients with ESRD or to native GLP‐1 severe renal impairment Liraglutide Acylated analog of human GLP‐1; 8–12 h None Mainly metabolized by 97% homology to native GLP‐1 13 h ppyroteolytic degg;radation; use caution in patients with renal impairment Exenatide QW Exenatide suspended in PLG 2–5 wk None Renal microspheres NR Albiglutide GLP‐1 dimer genetically fused to 3–5 d NR NR human albumin 6–7 d Dulaglutide GLP‐1 IgG4‐Fc fusion protein ~70 h NR NR ~4 d Lixisenatide Extendin‐4‐like GLP‐1 agonist ~2 h NR Renal modified C‐terminally ~3 h

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 See page 120 for enlarged view for GLP‐1 Agonists

Initial Dose Agent (Duration) Regular Dose Dose Frequency and Timing Exenatide BID 5 µg (1 month) 5 µg or Twice daily; given within 60‐minute period 10 µg before morning and evening meals Liraglutide 0.6 mg 1.2 mg or Once daily; any time of day (1 week) 1.8 mg 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 specified 1.5 mg

Lixisenatide. 10 µg 20 µg Once daily; within 60 min before breakfast (2 weeks)

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 See page 121 for enlarged view of DPP‐4 Inhibitors

Ex Vivo DPP‐4 Inhibition, % 24 h Agent Maximum Postdose Metabolism Elimination Linagliptin ~80% ~70 ~90% eliminated Biliary (>70% unchanged as unchanged; exposure parent), <6% via kidney decreased by CYP3A4 or P‐gp inducers

Saxagliptin ~80% ~70 Hepatically metabolized Renal (12%‐29% as parent, to active metabolite via 21%‐52% as metabolite) CYP3A4/5

Sitagliptin ~97% ~80 Not appreciably Renal (>80% unchanged as metabolized parent) Alogliptin ~90% ~75 Not appreciably Renal (>70% unchanged as metabolized parent)

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

106 See page 121 for enlarged view 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

Moderate Severe Renal Renal Impairment or Agent 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 pppostprandial glucose • Decreases A1c by 0.4% (~10‐15 mg/dl) • Most common adverse effects • Nausea, vomiting • Headache • Fatigue • Hypotension • ↓ TG Scranton 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 glucose Decreases A1c by 06%0.6% (15(~15‐20 mg/dl; more posttdil)prandial) • 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

107 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 ◦ 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.

108 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…………….

109 Some Agents in the Pipeline

• Sodium glucose cotransporter (SGLT‐2) inhibitors • Ultra‐long‐acting insulin • Insulin & GLP‐1 agonist combination • GPR119 agonists • Free fatty acid receptor‐1 (FFAR‐1) agonist

SGLT‐2

• SGLT‐2 (only) – Dapagliflozin – Canagliflozin – Empagliflozin – Ipraglifl oz in – 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.

110 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

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

SGLT‐2 Inhibitors Adverse 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

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

Insulin

• Ultra‐long‐acting Insulin – Degludec – Degludec Plus • Insulin & GLP‐1 combination – Degludec + Liraglutide – Glargine + Lixisenatide

111 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‐200 o Less hypoglycemic events o Less weight gain o 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

NPH (10–20 hr) Degludec (> 26 hr) Levels

n DiDetemir (< 24 h)hr) Insuli

Glargine (< 24 hr) Plasma

0 246810 12 14 16 18 20 22 24 Time (hours)

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

Basal Insulin Degludec Flat, Stable Profile of Both 100 Unit/ml and 200 Unit/ml Formulations

GIR: Glucose infusion rate Heise 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.

112 Degludec Plus

 Degludec Plus – Basal degludec + bolus boost of aspart –Clinical trial reports (BOOST)

 Once daily dosing – Degludec + aspart prior to evening meal –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 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 • Increase in post ‐meal GLP‐1 and GIP in T2DM • Not associated with hypoglycemia

GIP = gastric insulinotropic peptide

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

113 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 glucose‐stimu la te d iilinsulin 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 + lifestyle –TZD + GLP‐1 agonist + lifestyle

• β‐cell function can be preserved for 3.5 years after diagnosis of T2DM – Combination therapy o Complementary mechanisms

Key Points of Discussion at the 2012 ADA Scientific Sessions

• 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

114 WUZZLE #3

Key Points of Discussion at the 2012 ADA Scientific Sessions

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

115 What questions can I answer for you?

[email protected]

116 Healthy eating, weight control, increased physical activity Initial drug monotherapy Metformin Efficacy ( HbA1c) high Hypoglycemia low risk Weight neutral/loss Side effects GI / lactic acidosis Costs 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 + + + + + Two drug Sulfonylurea† Thiazolidine- DPP-4 GLP-1 receptor Insulin (usually combinations* dione Inhibitor agonist basal)

or DPP-4-i or DPP-4-i or TZD or TZD or DPP-4-i

or GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or 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:

More complex # insulin strategies Insulin (multiple daily doses) Inzucchi SE et al. Diabetes Care. 2012; 35:1364‐79.

117 Weight β‐cell CVD Other Considerations Hypoglycemia Cost Effect protection benefits

‐glucosidase GI adverse effects (gas), neutral low risk possible possible $ to $$ inhibitors (AGI) dose frequency

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

Dopamine neutral GI adverse effects (nausea) , low risk unknown yes/no $$$ agonist or loss hypotension, dizziness

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

TZD’s 4‐8 weeks for response, redistribution of subcutaneous/visceral fat, (glitazones) gain low risk possible yes/no $$ edema, bone loss, fracture, bladder cancer

118 Glucose Lowering Comparison Monotherapy Route of Target glucose: A1c (%) Administration FPG or PPG 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 Oral PPG 0.5-1.0 Inhibitors 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 ‐ PPG 0.8-1.5 Long‐acting ‐ both Amylin analogs Injectable PPG 0.6 Insulin Injectable Basal ‐ FPG Open to target Bolus ‐ PPG Adapted from Unger J et al. Postgrad Med. 2010; 122:145‐57. Cornell S et al. Postgrad Med. 2012; 124:84‐94.

119 Pharmacologic and Pharmacokinetic Differences among GLP‐1 Agonists

Active Metabolites, Significant

Agent Description Tmax, t1/2 Interactions Elimination Exenatide BID Synthetic analog of extendin‐4 2.1 h None Mainly renal; not found in saliva of Heloderma 2.4 h recommended for suspectum (lizard); 53% homology patients with ESRD or to native GLP‐1 severe renal impairment Liraglutide Acylated analog of human GLP‐1; 8–12 h None Mainly metabolized by 97% homology to native GLP‐1 13 h proteolytic degradation; use caution in patients with renal impairment Exenatide QW Exenatide suspended in PLG 2–5 wk None Renal microspheres NR Albiglu tide GLP‐1 dimer gtillgenetically fdfused to 3–5 d NR NR human albumin 6–7 d Dulaglutide GLP‐1 IgG4‐Fc fusion protein ~70 h NR NR ~4 d Lixisenatide Extendin‐4‐like GLP‐1 agonist ~2 h NR Renal modified C‐terminally ~3 h

Approved and Standard Investigational Doses for GLP‐1 Agonists

Lixisenatide. 10 µg 20 µg Once daily; within 60 min before breakfast (2 weeks)

120 Pharmacologic and Pharmacokinetic Characteristics of DPP‐4 Inhibitors

Saxagliptin ~80% ~70 Hepatically metabolized Renal (12%‐29% as parent, to active metabolite via 21%‐52% as metabolite) CYP3A4/5

Sitagliptin ~97% ~80 Not appreciably Renal (>80% unchanged as metabolized parent) Alogliptin ~90% ~75 Not appreciably Renal (>70% unchanged as metabolized parent)

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

Moderate Severe Renal Renal Impairment or Agent 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 CYP334/5A4/5 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.

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

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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.

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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.

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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.

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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.

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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.

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

SELF–ASSESSMENT CROSSWORD PUZZLE

Across: Down: 3 ‐ Generic name for newly approved long‐acting 1 ‐ A new class of drugs that decreases renal insulin absorption of glucose 5 ‐ The good fat 2 ‐ Oral agent with most hypoglycemic risk 6 ‐ Drug with the best A1c lowering potential 4 ‐ The best pharmacotherapy approach 7 ‐ Popular incretin hormone 8 ‐ Hormone that affects neuro‐endocrine 9 ‐ Critical undesirable drug side effect rhythm 9 ‐ The pre‐meal blood glucose goal is 140‐ 180 mg/dL for patients in this setting

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

126