Duality Statement

10/28/2016

Improving Patient Outcomes with Individualized Therapy in the Management of Type 2 Diabetes

Timothy S. Reid, M.D. Mercy Diabetes Center Janesville, WI

Duality Statement

• Dr. Reid is a Speaker and Consultant for the following organizations: – Novo Nordisk – Lilly – Sanofi – Janssen

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Diabetes Mellitus in the US

29.1 million Americans 86 million Americans age have diabetes (2012) 20 and older have pre‐ 9.3% of the population diabetes

8.1 million Americans with 7th leading cause of death Diabetes are undiagnosed in US

In seniors (age 65 and 1.4 million new diagnosis older) the prevalence is annually 25.9%

American Diabetes Association: www.diabetes.org/diabetes‐basics/statistics/ (Accessed 9/7/2016)

Oral Antihyperglycemic Agents empagliflozin dapagliflozin alogliptin metformin miglitol glimepiride repaglinideAre you feeling confused withsaxagliptin all of the choicesbromocriptine in diabetes medications? glyburide pioglitazone sitagliptin glipizide linagliptin colesevelam acarbose rosiglitazone nateglinide canagliflozin

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HTN and Diabetes Drug Classes in the US over the past 90 Years

12 SGLT-2 Renin Inhibitors Inhibitors

11 Angiotensin II Dopamine Agonists Receptor Blockers 10 Bile Acid Sequestrants ACE Inhibitors 9 DPP-4 Receptor Antagonists 8 Amylinomimetics Calcium Channel Peripheral -1 Blockers 7 GLP-1 Receptor Blockers Agonists -blockers 6 Meglitinides

5 Thiazolidinediones Diuretics Central -2 Adrenergic Agonists 4 -glucosidase Inhibitors neuronal blockers (Phenformin) 3 Withdrawn Biguanides

Number of Medication Classes Number of Medication 1978 2 Insulin Sulfonylureas 1 Vasodialators

1920’s 1950’s 1960’s 1970’s 1980’s 1990’s 2000’s 2010’s

Spheres of Concern

Hypoglycemia CV Risk Reduction Renal/UTI/Genital

Patient

Weight Economic Gastrointestinal

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Do Patients Come to You:

Excited? Fearful? Happy? Hesitant? Committed? Hopeful? Dreading?

What can we do to improve this?

When Patients Come to You:

The Words We Use Can Have a Mighty Impact.

Our Body Language Tells More Than Our Words.

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When Patients Come to You:

Leave Some Hope With The Patient.

Never Say Never.

Work With The Patient’s Priorities

Healthy eating, wt. control, increased physical activity & diabetes education

• Diabetes Self‐Management Education – improved diabetes knowledge – improved self‐care behavior – improved clinical outcomes • lower A1C • lower self‐reported weight • improved quality of life American Diabetes • healthy coping Association. Approaches to glycemic treatment . Sec. 7. In Standards of Medical Care • lower costs in Diabetes – 2015. Diabetes Care 2015;38(Suppl. 1):S41‐ S48.

American Diabetes Association. Approaches to glycemic treatment . Sec. 7. In Standards of Medical Care in Diabetes – 2015. Diabetes Care 2015;38(Suppl. 1):S20‐S21.

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Approaches to Glycemic Treatment

• Pharmacological Therapy for Type 2 DM – Metformin is preferred if tolerated and not contraindicated – Consider Insulin if symptomatic or blood sugars high – Advance therapy q3 months if not at goal – Patient centered approach to therapy – T2DM is progressive. Insulin therapy will eventually be needed in most cases

American Diabetes Association. Approaches to glycemic treatment . Sec. 7. In Standards of Medical Care in Diabetes – 2015. Diabetes Care 2015;38(Suppl. 1):S41‐S48.

Healthy eating, wt. control, increased physical activity & diabetes education Metformin Efficacy…………………… High Efficacy Hypo Risk……………….. Low Hypoglycemic Risk Weight………………..….. Weight Neutral Side Effects………….….. Lactic Acidosis/GI intolerance Cost…………………….… Low Cost

If A1c target not achieved after ~3 months of monotherapy, proceed to 2‐drug combination (order not meant to denote any specific preference –choice dependent on a variety of patient and disease specific factors).

American Diabetes Association. Approaches to glycemic treatment . Sec. 7. In Standards of Medical Care in Diabetes – 2015. Diabetes Care 2015;38(Suppl. 1):S41‐ S48.

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Metformin Metformin Metformin Metformin Metformin Metformin + + + + + +

Sulfonylurea Thiazolidinedione DPP‐4 Inhibitor SGLT‐2 Inhibitor GLP‐1 Receptor Insulin (basal) Efficacy………………… High….………………. high…………………. Intermediate.………. Intermediate.………. high…………….…….Agonist Highest Hypo Risk…………….. Moderate risk………. low Risk…………….. Low risk.……………. Low risk……………… Low risk……………… High risk Weight……………..….. gain…………….…….. Gain…………………. neutral……………….. losing………………… losing……………….. gain Side Effects……….….. hypoglycemia………. Edema,CHF,Fx’s……Low… rare…………………… GU, dehydration……. GI………………….…. hypoglycemia Cost………………….… Low.…………………… ……………… high…………………… high…………………… high…………………… variable

If A1c target not achieved after ~3 months of dual therapy, proceed to 3‐drug combination (order not meant to denote any specific preference –choice dependent on a variety of patient and disease‐specific factors).

American Diabetes Association. Approaches to glycemic treatment . Sec. 7. In Standards of Medical Care in Diabetes – 2015. Diabetes Care 2015;38(Suppl. 1):S41‐ S48.

Metformin Metformin Metformin Metformin Metformin Metformin + + + + + +

Sulfonylurea Thiazolidinedione DPP‐4 Inhibitor SGLT‐2 Inhibitor GLP‐1 Receptor Insulin (basal) Efficacy………………. High….………………. high…………………. Intermediate.………. Intermediate.………. high…………….…….Agonist Highest Hypo Risk……………. Moderate risk………. low Risk…………….. Low risk.……………. Low risk……………… Low risk……………… High risk Weight……………….. gain…………….…….. Gain…………………. neutral……………….. losing………………… losing……………….. gain Side Effects…………. hypoglycemia………. Edema,CHF,Fx’s…… rare…………………… GU, dehydration……. GI………………….…. hypoglycemia Cost…………………… Low.…………………… Low Cost………………… high…………………… high…………………… high…………………… variable

Metformin Metformin Metformin Metformin Metformin Metformin + + + + + + American Diabetes Sulfonylurea Thiazolidinedione DPP‐4 Inhibitor SGLT‐2 Inhibitor GLP‐1 Receptor Insulin (basal) Agonist Association. Approaches to TZD SU SU SU glycemic treatment . Sec. 7. SU TZD DPP‐4 i In Standards of Medical Care DPP‐4 i TZD TZD TZD DPP‐4 i in Diabetes – 2015. Diabetes SGLT‐2 i SGLT‐2 i SGLT‐2 i DPP‐4 i Care 2015;38(Suppl. 1):S41‐ Insulin SGLT‐2 i GLP‐1 RA S48. GLP‐1 RA Insulin Insulin GLP‐1 RA Insulin Insulin

If A1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP‐ RA, add basal insuin; or (3) on optimally titrated basal insulin, add GLP‐1 RA or mealtime insulin. In refractory patients, consider adding TZD or SGLT‐2i:

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Metformin Metformin Metformin Metformin Metformin Metformin + + + + + +

Metformin + Insulin (basal) + Mealtime Insulin or GLP‐1 RA

Garber AJ et al. Endocr Pract. 2013;19(Suppl 2):1‐48.

GarberGarber AJ, AJ, et et al. al. Endocr Endocr Pract Pract. 2015;21(4):438. 2015;21(4):438‐447.‐447.

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Things Patients Never Say:

Doc, My Diabetes Algorithm is Off. IMy Myseldom GrandmotherCanLDL CholesterolYouuse Fixmy It?insulin. and Hurts Uncle I don’t had a exercisehorrible and painful I eat atdeath odd ashours. a result Can of their diabetesLife asyou I know and fix me?I itam is over…..right?afraid this will happen to me….

New Therapeutic Classes

• 9 classes of oral medication • 4 classes of subcutaneous medications • New Concentrated Insulins • Insulin/GLP‐1 Combinations • New classes coming…..

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Where Diabetes Medications Work

GLP‐1 GLP‐1 Insulin Insulin

GLP‐1 Insulin Insulin

GLP‐1 GLP‐1 Insulin Insulin Insulin

DeFronzo RA. Diabetes. 2009;58 (4): 773-795.

Where Diabetes Medications Work

GLP‐1 GLP‐1 Insulin Insulin

GLP‐1 Insulin Insulin

GLP‐1 GLP‐1 Insulin Insulin Insulin

DeFronzo RA. Diabetes. 2009;58 (4): 773-795.

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Class Generic Name Trade Name

α‐glucosidase Inhibitor acarobose, miglitol Precose, Glyset

amylinomimetics amylin Symlin

biguanides metformin Glucophage, Riomet

Bile Acid Sequestrants colesevelam WelChol

Dopamine Agonists bromocriptine Cycloset

alogliptin, linagliptin Nesina, Tradjenta DPP‐4i saxagliptin, sitagliptin Onglyza, Januvia albiglutide, dulaglutide Tanzeum, Trulicity, Byetta GLP‐1 Agonists exenatide, liraglutide Victoza

Glucagon glucagon Glucagon

Insulin Humulin, Novolin, Humalog, Novolog, Apidra, insulin (various) Lantus, Levemir

meglitinides nateglinide, repaglinide Starlix, Prandin

SGLT‐2i canagliflozin, dapagliflozin, empagliflozin Invokana, Farxiga, Jardiance

Sulfonylureas glimepiride, glipizide glyburide Amaryl, Glucotrol, Diabeta, Micronase

Thiazolidinediones pioglitazone, rosiglitazone Actos, Avandia asdf

Oral Diabetes Medications   Pancreatic   Renal  Insulin Hepatic  GI CHO β-cell Glucagon Peripheral Reabsorp-tion Secretion Glucose Absorption Function Secretion Glucose Uptake of Glucose Production

-Glucosidase ✔  Inhibitor

 Biguanide ✔✔

Bromocriptine Unknown Colesevelam Unknown

DPP-4 ✔ ✔ Improve Inhibitor *

Glinide ✔ 

SGLT-2 Inhibitor ✔

SU ✔ ✔ 

TZD ✔✔ Improve

National Diabetes Education Program. Available at: http://www.ndep.nih.gov/media/Drug_tables_supplement.pdf Accessed August 10, 2010 . Nathan DM, et * In vitro and al. Diabetes Care. 2009;32:193‐203. Rodbard HW, et al. Endocr Pract. 2009;15(6):540‐559. Januvia [prescribing information]. Whitehouse Station, NJ: Merck & rodent data; Co., Inc.; 2010. Onglyza [prescribing information]. Princeton, NJ: Bristol‐Myers Squibb Co.; 2009. Welchol [prescribing information]. Parsippany, NJ: Daiichi preliminary Sankyo Inc.; 2011.. Cycloset [prescribing information]. San Diego, CA: Santarus, Inc.; 2010. human data

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Metformin Metformin Metformin Metformin Metformin Metformin + + + + + +

Metformin + Insulin (basal) + Mealtime Insulin or GLP‐1 RA

The Incretin System

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Multiple Sites of Actions of Incretins

Hormone that stimulates insulin secretion in response to oral carbohydrate intake • GLP‐1 • GIP

This action impacts multiple sites of glucose regulation • Suppression of glucagon at the pancreatic  cell • Stimulates insulin release at the pancreatic  cell • Promotes satiety and reduce appetite in CNS • Slows gastric emptying DPP‐4 inactivates native GLP‐1 • Works quickly

Current Stable of GLP‐1 agonists

Twice Daily Once Daily Once Weekly

Exenatide Liraglutide Albiglutide Lixisenatide Dulaglutide (FDA Approved 7/28/2016)1 Exenatide LAR

Semaglutide (oral) (Investigational)

1. FDA Press Release: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513602.htm (Accessed 9/18/2016)

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Current Stable of GLP‐1 agonists % Patients Expected A1c Fasting BGM Generic Name Dosage Reaching <7% Reduction Reduction A1c 30 mg/wk ‐0.7% ‐16 mg/dl Albiglutide 50 mg/wk ‐0.9% ‐25 mg/dl 5 mcg/BID ‐0.7% ‐17 mg/dl 48% Exenatide IR 10 mcg BID ‐0.9% ‐19 mg/dl 53% 2 mg subQ Exenatide LAR ‐1.6% ‐25 mg/dl 58% weekly 0.75 mg/weekly ‐0.7% ‐26 mg/dl Dulaglutide 1.5 mg/weekly ‐0.8% ‐29 mg/dl 1.2 mg/d ‐0.8% ‐15 mg/dl Liraglutide 1.8 mg/d ‐1.1% ‐26 mg/dl 10 mcg/d Transition Dose Lixisenatide 20 mcg/d ‐0.83% ‐15.84 mg/dl 44% https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM‐PI‐MG‐IFU‐COMBINED.PDF http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021773s9s11s18s22s25lbl.pdf

Current Stable of GLP‐1 agonists % Patients Expected A1c Fasting BGM Generic Name Dosage Reaching <7% Reduction Reduction A1c

Albiglutide 30 mg/wk ‐0.7% ‐16 mg/dl (Tanzeum) 50 mg/wk ‐0.9% ‐25 mg/dl

Exenatide IR 5 mcg/BID ‐0.7% ‐17 mg/dl 48% (Byetta) 10 mcg BID ‐0.9% ‐19 mg/dl 53% 2 mg subQ Exenatide LAR ‐1.6% ‐25 mg/dl 58% (Bydureon) weekly

Dulaglutide 0.75 mg/weekly ‐0.7% ‐26 mg/dl (Trulicity) 1.5 mg/weekly ‐0.8% ‐29 mg/dl

Liraglutide 1.2 mg/d ‐0.8% ‐15 mg/dl (Victoza) 1.8 mg/d ‐1.1% ‐26 mg/dl

Lixisenatide 10 mcg/d Transition Dose (Adlyxin) 20 mcg/d ‐0.83% ‐15.84 mg/dl 44% https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM‐PI‐MG‐IFU‐COMBINED.PDF http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021773s9s11s18s22s25lbl.pdf

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GLP‐1’s and Safety

• Risks: • GI upset: Nausea, Vomiting, Diarrhea

• Pancreatitis • Renal Impairment • Medullary Thyroid Carcinoma (Rats and Mice) • Hypersensitivity • Hypoglycemia (esp. with insulin and sulfonylureas)

GLP‐1’s and Safety

• Choosing the Right Patient: Exclusions – Personal Hx of Pancreatitis or high risk of developing pancreatitis – Gastroparesis – Severe Renal Disease – Personal or Family Hx of Medullary Thyroid Carcinoma – Personal or Family Hx of MEN‐2 (thyroid, parathyroid and adrenal tumors)

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Current Basal Insulins

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How Do You Approach The Insulin Discussion? • Insulin is a 4‐letter word • Patients: – Can be injection adverse – Fearful of losing control of life and scheduling – Fearful of the “End of the Road” – The Unknown • Use All of Your Resources

Metformin Metformin Metformin Metformin Metformin Metformin + + + + + +

Metformin + Insulin (basal) + Mealtime Insulin or GLP‐1 RA

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Current Basal Insulins

Once Daily Twice Daily

Degludec1 U‐100 Detemir2 U‐100 U‐200 (NPH5)U‐100 Detemir2 U‐100 Glargine3,4 U‐100 U‐300

1. http://www.novo‐pi.com/tresiba.pdf (Accessed 9/30/2016) 2. http://www.novo‐pi.com/levemir.pdf (Accessed 9/30/2016) 3. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdf (Accessed 9/30/2016) 4. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206538lbl.pdf (Accessed 9/30/2016) 5. http://pi.lilly.com/us/HUMULIN‐N‐USPI.pdf (Accessed 9/30/2016)

Current Basal Insulins

Expected A1c Fasting BGM Generic Name Concentration Reduction Reduction

Degludec1 U‐100 ‐0.7% ‐16 mg/dl U‐200 ‐0.9% ‐25 mg/dl

2 Detemir U‐100 ‐2.0% ‐69 mg/dl

3 Glargine U‐100 ‐0.46% ‐49 mg/dl U‐3004 ‐0.9% ‐29 mg/dl

(NPH) (typically twice daily dosing)5 U‐100

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Current Basal Insulins

Expected A1c Fasting BGM Generic Name Concentration Reduction Reduction

Degludec1 U‐100 ‐0.7% ‐16 mg/dl (Tresiba) U‐200 ‐0.9% ‐25 mg/dl

2 Detemir U‐100 ‐2.0% ‐69 mg/dl (Levemir)

3 Glargine U‐100 ‐0.46% ‐49 mg/dl (Lantus, Toujeo) U‐3004 ‐0.9% ‐29 mg/dl

(NPH) (typically twice daily dosing)5 U‐100 (Novolin, Humulin)

Insulins in General

• Robust blood sugar reduction – A1c reductions 1.5‐3.5% • Few toxicities – Hypersensitivities – typically related to excipients – Hypoglycemia – requires monitoring and management – Antibodies – clinical significance ? – Lipodystrophy – Edema • Few Drug:Drug interactions – Most are changes in blood sugars, high or low • Delivery – Vial/Syringe – Pens – Pumps – Inhalation

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Safety and Basal Insulin

• Hypoglycemia – Especially when combined with secretogogues (SU’s, glinides) • Hypersensitivity • Weight Gain • Pen Sharing! • Inappropriate Dosing – Mixing Insulins – Mis‐Dosing

Why the New Insulins?

• Flatter Action Curves • Prolonged Insulin Activity • Smaller Insulin Depot • Suggestion of improved nocturnal hypoglycemia

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Confirmed Nocturnal or Severe Nocturnal Hypoglycemic Events (Weeks 9 to 6 months)

Edition 1Edition 2Edition 3 Gla‐300 36.1 (2.97) 21.6 (1.94) 16 (NS) % (Events/pt‐yr) Gla‐100 45.8 (4.05) 27.9 (3.19) 17 (NS) %(Events/pt‐yr) Relative Risk 0.79 0.77 0.89 [95%CI] Based on % [0.67,0.93]* [0.61,0.99]* [0.66,1.20] pts.

*Significant vs. Gla‐100 % = percentage of patients experiencing 1 event, NS = not shown

http://www.pbm.va.gov/PBM/clinicalguidance/drugmonographs/Insulin_glargine_300U_per_mL_TOUJEO.pdf (Accessed 10/1/2016)

Confirmed Nocturnal Hypoglycemic (Meta‐analysis): Degludec

Rate Ratio IDeg vs. GLA [95%CI] Dose Titration Maintenance End of Trial Period Period T2D Pooled Studies 0.68 [0.57, 0.82]* 0.81 [0.64,1.02] 0.62 [0.49, 0.78]* T1D Pooled Studies 0.83 [0.69, 1.00] 0.88 [0.72, 1.08] 0.75 [0.60, 0.94]* T2D and T1D 0.75 [0.65, 0.85]* 0.86 [0.74, 1.00] 0.68 [0.58, 0.80]* Pooled Studies *Significant vs. Gla‐100

http://www.pbm.va.gov/PBM/clinicalguidance/drugmonographs/Insulin_Degludec_Tresiba_Monograph.pdf (Accessed 10/1/2016) Russel‐Jones, et al. Nutrition Metab Cardiovasc Dis; 2015.

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Metformin Metformin Metformin Metformin Metformin Metformin + + + + + +

Metformin + Insulin (basal) + Mealtime Insulin or GLP‐1 RA

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Rationale for Basal Insulin/GLP‐1

• Balanced Approach to Fasting and Prandial glucose coverage • Replace insulin for fasting/underlying glycemic control • Up‐regulating native gut metabolism to glucose stimulation • Easier for patient than MDI insulin management • Overall reduced risk of hypoglycemia vs. MDI

Where Diabetes Medications Work

GLP‐1 GLP‐1 Insulin Insulin

GLP‐1 Insulin Insulin

GLP‐1 GLP‐1 Insulin Insulin Insulin

DeFronzo RA. Diabetes. 2009. 58 (4): 773-795.

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Effect of Insulin Glargine Up‐Titration vs. Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial

A1c = ‐1.81% Baseline A1c Wt = ‐1.4kg = 8.4% Hypoglycemia 2.23 278 Received 250 participants episodes/pt. Degludec/liraglutide completed year A1c <7% = 71.6% 767 Pts Screened 557 A1c = ‐1.13% Randomized Wt = +1.8kg Hypoglycemia 5.05 265 participants episodes/pt. 279 Received insulin year glargine +metformin completed A1c <7% = Baseline A1c 24.6% = 8.2%

26 Week Study Period Randomized, open‐label, treat to target

Lingvay I, Manghi F et. al. Effect of Insulin Glargine UP‐titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes. JAMA . 2016;315:898‐907.

Effect of Insulin Glargine Up‐Titration vs. Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial

Lingvay I, et al. Effect of Insulin Glargine Up‐titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes. JAMA . 2016;315(9):898‐907.

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Effect of Insulin Glargine Up‐Titration vs. Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial

Lingvay I, et al. Effect of Insulin Glargine Up‐titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes. JAMA . 2016;315(9):898‐907.

Effect of Insulin Glargine Up‐Titration vs. Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial

Lingvay I, et al. Effect of Insulin Glargine Up‐titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients with Uncontrolled Type 2 Diabetes. JAMA . 2016;315(9):898‐907.

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Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal‐Plus or Basal‐Bolus in Type 2 Diabetes: The GetGoal Duo‐2 Trial

Glargine + A1c 7.2% Lixisenatide +/‐ Symptomatic Hypoglycemia Metformin = 107

Metformin + Glargine + A1c 7.2% Glargine Glulisine Daily Symptomatic Hypoglycemia = 140 Optimization +/‐ metformin (P = 0.01 vs. Lixi)

Glargine + A1c 7.0% Glulisine 3x Symptomatic Hypoglycemia = 154 A1c improved daily +/‐ (P = 0.0001 vs. Lixi) from 8.5 to 7.9% metformin

12 Weeks 26 Weeks

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Dulaglutide + Glargine: AWARD‐9 Trial

• Presented at 76th American Diabetes Association Scientific Sessions

Fasting Blood Weight Change A1c reduction Sugar (kg) (mg/dl) Dulaglutide 1.5 mg + ‐1.44% 44.63 ‐1.91 glargine Placebo + glargine 0.67% 27.90 +0.50

Pozzilli P. Improved Glycemic Control and Weight Loss with Once‐Weekly Dulaglutide vs. Placebo, Both Added to Titrated Daily Insulin Glargine in Type 2 Diabetes Paitients (AWARD‐9). Presented at the 2016 American Diabetes Association Scientific Session June 10‐14th, 2016.

Advancing Basal Insulin Replacement in Type 2 Diabetes Inadequately Controlled with Insulin Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP‐1 Receptor Agonist, Versus Thrice‐Daily Prandial Insulin Lispro (Harmony‐6) • 26 week Study: Randomized, open‐label, active controlled trial • Once‐weekly albiglutide vs thrice‐daily insulin lispro added to titrated once‐daily glargine • Oral agents metformin and or pioglitazone could be continued

Rosenstock J. et al. Advancing Basal Insulin Replacement in Type 2 Diabetes Inadequately Controlled with Insulin Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP‐1 Receptor Agonist, Versus Thrice‐Daily Prandial Insulin Lispro. Diabetes Care 2014;37:2317‐2337.

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Albiglutide A1c = ‐0.82% Weight Change = ‐0.7kg 30/50 mg plus Hypoglycemia = 0.9 glargine/OAD’s events/pt/yr Metformin ± 285 pts pioglitazone and Glargine Optimization 3x daily prandial A1c = ‐0.66% Weight Change = +0.8kg Lispro + Hypoglycemia = 2.3 glargine/OAD’s events/pt/yr 281 pts

4‐8 Weeks 26 Weeks 8 Week Follow‐up

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Basal Insulin/GLP‐1

• Powerful new approach to patients with T2DM – Effective A1c reduction – Less hypoglycemia exposure – Potential for weight loss

Basal Insulin/GLP‐1 Agonist Patient Profile • Patient with T2DM • Has tried a number of oral agents/basal insulin • Possibly at hypoglycemic risk • No Hx of pancreatitis/MTC/MEN‐2 • Renal Status acceptable/stable • No Hx of gastroparesis/severe GI disturbance

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Summary:

• Type 2 Diabetes Mellitus has grown to epidemic proportions • The landscape of diabetes medications continues to expand • Opportunities for improved control of the disease state with fewer side effects and the potential for reduction of CV risk are growing • Combination therapy with newer agents that provide powerful synergy for our patients has the potential to change the landscape of Type 2 Diabetes management.