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ENDOCRINE SOCIETY PRESENTS SATURDAY, SEPTEMBER 12, 2015 6:15 – 7:15 AM Registration & Meal Service: 6:00 - 6:15 AM Intercontinental Miami Hotel Grand Ballroom This activity is supported by an educational grant from sanofi-aventis U.S. Inc. Sponsored by CME Credits: 1.0 AMA PRA Category 1 CreditUpdate in Basal Insulins: Your Questions Answered FACULTY Andrew J. Ahmann, MD, OREGON HEALTH AND SCIENCE UNIVERSITY AGENDA Update in Basal Insulins: Overview of benefits and challenges of insulin initiation Newly approved insulin glargine U-300 (concentrated basal insulin) Emerging PEGylated insulin lispro (LY2605541) Emerging insulin degludec (ultra-long-acting insulin) • Head-to-head summary Question Review and Clinical Case Presentation Audience Q&A and Closing LEARNING OBJECTIVES Evaluate the benefits of initiating insulin therapy and summarize common barriers to basal insulin therapy Summarize benefits and limitations of new and emerging basal insulins Select among basal insulin and non-insulin therapies to improve glycemic outcomes and minimize adverse effects taking individual patient contexts into consideration

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Page 1: Update in Basal Insulins › sites › default › files...Basal Insulin Use • Type 1 diabetes • Long‐acting basal analogues are standard • Used with rapid acting analogs in

E N D O C R I N E S O C I E T Y P R E S E N T S

SATURDAY, SEPTEMBER 12, 20156:15 – 7:15 AMRegistration & Meal Service: 6:00 - 6:15 AM

Intercontinental Miami Hotel Grand Ballroom

This activity is supported by an educational grant from sanofi-aventis U.S. Inc.Sponsored by

CME Credits: 1.0 AMA PRA Category 1 Credit™

Update in Basal Insulins: Your Questions Answered

FACULTYAndrew J. Ahmann, MD, OREGON HEALTH AND SCIENCE UNIVERSITY

AGENDAUpdate in Basal Insulins:• Overview of benefits and challenges of insulin initiation • Newly approved insulin glargine U-300 (concentrated basal insulin)• Emerging PEGylated insulin lispro (LY2605541)• Emerging insulin degludec (ultra-long-acting insulin)• Head-to-head summaryQuestion Review and Clinical Case PresentationAudience Q&A and Closing

LEARNING OBJECTIVES• Evaluate the benefits of initiating insulin therapy and summarize

common barriers to basal insulin therapy• Summarize benefits and limitations of new and emerging basal

insulins• Select among basal insulin and non-insulin therapies to improve

glycemic outcomes and minimize adverse effects taking individual patient contexts into consideration

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SYMPOSIUM AGENDA 6:00 – 6:15 AM Registration & Meal Service 6:15 – 6:20 AM Welcome and Introduction

Andrew J. Ahmann, MD 6:20 – 6:55 AM Symposium

• Overview of benefits and challenges of insulin initiation • Newly approved insulin glargine U-300 (concentrated basal insulin) • Emerging PEGylated insulin lispro (LY2605541) • Emerging insulin degludec (ultra-long-acting insulin) • Head-to-head summary Andrew J. Ahmann, MD

6:55 – 7:05 AM Question Review and Clinical Case Presentation 7:05 – 7:15 AM Audience Q&A and Closing Remarks

FACULTY Andrew J. Ahmann, MD Professor of Medicine Director, Harold Schnitzer Diabetes Health Center Oregon Health & Science University Portland, Oregon

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ACCREDITATION STATEMENT The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Endocrine Society has achieved Accreditation with Commendation. The Endocrine Society designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

LEARNING OBJECTIVES Upon completion of this educational activity, learners will be better able to:

• Evaluate the benefits of initiating insulin therapy and summarize common barriers to basal insulin therapy

• Summarize benefits and limitations of new and emerging basal insulins • Select among basal insulin and non-insulin therapies to improve glycemic outcomes and

minimize adverse effects taking individual patient contexts into consideration

TARGET AUDIENCE This continuing medical education activity should be of substantial interest to endocrinologists, endocrine fellows, and healthcare professionals who treat patients with diabetes.

STATEMENT OF INDEPENDENCE As a provider of continuing medical education (CME) accredited by the Accreditation Council for Continuing Medical Education, the Endocrine Society has a policy of ensuring that the content and quality of this educational activity are balanced, independent, objective, and scientifically rigorous. The scientific content of this activity was developed under the supervision of the Endocrine Society's Special Programs Committee (SPC). The commercial supporter(s) of this activity have no influence over the planning of this CME activity.

DISCLOSURE POLICY The faculty, committee members, and staff who are in position to control the content of this activity are required to disclose to the Endocrine Society and to learners any relevant financial relationship(s) of the individual or spouse/partner that have occurred within the last 12 months with any commercial interest(s) whose products or services are related to the CME content. Financial relationships are defined by remuneration in any amount from the commercial interest(s) in the form of grants; research support; consulting fees; salary; ownership interest (e.g., stocks, stock options, or ownership interest excluding diversified mutual funds); honoraria or other payments for participation in speakers' bureaus, advisory boards, or boards of directors; or other financial benefits. The intent of this disclosure is not to prevent CME planners with relevant financial relationships from planning or delivery of content, but rather to provide learners with information that allows them to make their own judgments of whether these financial relationships may have influenced the educational activity with regard to exposition or conclusion. The Endocrine Society has reviewed all disclosures and resolved or managed all identified conflicts of interest, as applicable.

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The faculty reported the following relevant financial relationship(s) during the content development process for this activity: Andrew J. Ahmann, MD: Consultant, Lilly, Sanofi; Research Grant Support, Novo Nordisk

The following SPC member who reviewed content for this activity reported relevant financial relationships: Guillermo E Umpierrez, MD, CDE: Advisory Board and Consultant, Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Regeneron, Sanofi; Research Grant Support, Boehringer Ingelheim, Merck & Co., Novo Nordisk, Regeneron The following SPC Committee members reported relevant financial relationships: Sarah Berga, MD: Advisory Board Member, Agile Therapeutics, Noven Pharmaceuticals, Inc., Watson Pharmaceuticals, Teva Pharmaceuticals Industries, Shionogi, Inc.; Consultant, AHC Media, LLC, Shionogi, Inc. Paresh Dandona, MD, PhD, FRCP: Consultant and Speaker, AstraZeneca, Bristol Myers Squibb, Janssen, Merck, Novo Nordisk Irl B Hirsch, MD: Consultant, Abbott Laboratories, Becton Dickinson, Roche Diagnostics; Grant Support, Halozyme, Sanofi E. Michael Lewiecki, MD: Consultant, Amgen, Eli Lilly, Merck, Radius Health, AgNovos Healthcare, Theranova; Research Grant Support, Amgen, Eli Lilly, Merck Lisa Nachtigall, MD: Consultant, Genentech; Consultant and Principal Investigator, Ipsen Amy Rothberg, MD: Consultant, Novo Nordisk; Speaker, Takeda Pharmaceuticals The following SPC members reported no relevant financial relationships: John Carmichael, MD; Natalie Cusano, MD; Larry Fox, MD; Michael S Irwig, MD; Connie B Newman, MD Endocrine Society staff associated with the development of content for this activity reported no relevant financial relationships.

DISCLAIMER The information presented in this activity represents the opinion of the faculty and is not necessarily the official position of the Endocrine Society. Use of professional judgment: The educational content in this activity relates to basic principles of diagnosis and therapy and does not substitute for individual patient assessment based on the health care provider’s examination of the patient and consideration of laboratory data and other factors unique to the patient. Standards in medicine change as new data become available. Drugs and dosages: When prescribing medications, the physician is advised to check the product information sheet accompanying each drug to verify conditions of use and to identify any changes in drug dosage schedule or contraindications.

POLICY ON UNLABELED/OFF-LABEL USE The Endocrine Society has determined that disclosure of unlabeled/off-label or investigational use of commercial product(s) is informative for audiences and therefore requires this information to be disclosed to the learners at the beginning of the presentation. Uses of specific therapeutic agents, devices, and other products discussed in this educational activity may not be the same as those indicated in product labeling approved by the Food and Drug Administration (FDA). The Endocrine Society requires that any discussions of such “off-label” use be based on scientific research that conforms to generally accepted standards of

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experimental design, data collection, and data analysis. Before recommending or prescribing any therapeutic agent or device, learners should review the complete prescribing information, including indications, contraindications, warnings, precautions, and adverse events.

PRIVACY AND CONFIDENTIALITY STATEMENT The Endocrine Society will record learner's personal information as provided on CME evaluations to allow for issuance and tracking of CME certificates. The Endocrine Society may also track aggregate responses to questions in activities and evaluations and use these data to inform the ongoing evaluation and improvement of its CME program. No individual performance data or any other personal information collected from evaluations will be shared with third parties.

ACKNOWLEDGEMENT OF COMMERCIAL SUPPORT This activity is supported by an educational grant from sanofi-aventis U.S. Inc.

AMA PRA CATEGORY 1 CREDIT™ (CME) INFORMATION The Endocrine Society designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. To receive a maximum of 1.0 AMA PRA Category 1 Credits™ participants must complete the activity evaluation online at education.endocrine.org/DM2CEU15 by October 30, 2015. After completing the evaluation, you will be able to save or print a CME certificate. For questions about content or obtaining CME credit, please contact the Endocrine Society at education.endocrine.org/contact.

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FACULTY BIOGRAPHY

Andrew Ahmann, MD Dr. Andrew Ahmann is Professor of Medicine at Oregon Health and Science University (OHSU) in Portland, Oregon. He is the Director of the Harold Schnitzer Diabetes Health Center, a combined pediatric and adult comprehensive diabetes center for patient care and clinical research. He is also Director of Diabetes Services at OHSU. As an endocrinologist/ diabetologist, Dr. Ahmann has remained active in patient care, medical education, advocacy, professional organizations and clinical research.

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Update In Basal Insulins:Your Questions Answered

Andrew Ahmann, MD

Harold Schnitzer Diabetes Health CenterProfessor of Medicine

Oregon Health Sciences University

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Objectives

• Evaluate the benefits of initiating insulin therapy and summarize barriers to basal insulin therapy

• Summarize benefits and limitations of new and emerging basal insulins

• Select among basal insulin and non‐insulin therapies to improve glycemic outcomes and minimize adverse effects taking individual patient contexts into consideration

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Basal Insulin Use

• Type 1 diabetes • Long‐acting basal analogues are standard• Used with rapid acting analogs in basal‐bolus therapy

• Type 2 diabetes• Basal insulin added to non‐insulin agents is standard• Basal‐bolus therapy with rapid acting analogs is effective therapy as β‐cell function deteriorates

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UKPDS: Over Time, Need for Exogenous Insulin Increases

Wright A, et al. UKPDS. Diabetes Care. 2002;25:330–336.

Patients Requiring Insulin (%)

20

40

60

01 2 4 5

Years From Randomization3 6

ChlorpropamideGlyburide

Oral agentsBy 6 years, more than 50% of UKPDS patients required insulintherapy

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When to Consider Basal Insulin in Type 2 Diabetes

• Basal insulin may be second agent after metformin

• When combination oral/injectable agents become inadequate A1C >7.0‐)

• High FPG • Unacceptable side effects of other agents • Patient with advanced hepatic or renal disease

FPG = fasting plasma glucose 

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ADA/EASD 2015 Guidelines: Basal Insulin Use

SGLT2‐i = sodium‐glucose cotransporter 2 inhibitor; GLP‐1 RA = glucagon‐like peptide‐1 receptor agonists.Adapted from American Diabetes Association. Diabetes Care. 2015;38(suppl 1):S41‐S48.

Basal Insulin + Mealtime insulin or GLP-1 RA

If combination therapy that includes basal insulin has failed to achieve A1C target after 3-6 months,proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents

Metformin +GLP-1 RA +

SU

TZD

Insulin

or

or

If needed to reach individualized A1C target after ~3 months, proceed to 3-drug combination(order not meant to denote specific preference)

Metformin +SU

highmoderate riskgainhypoglycemialow

Metformin +TZD

highlow riskgainedema, HF, fx’shigh

Metformin +DPP-4-i

intermediatelow riskneutralrarehigh

Metformin +GLP-1 RA

highlow risklossGIhigh

Metformin +Insulin (basal)

highesthigh riskgainhypoglycemiavariable

Metformin +SGLT2-i

intermediatelow riskneutralrarehigh

Metformin +SU+

TZD

DPP-4-i

GLP-1-RA

Insulin

or

or

or

SGLT2-i

or

Metformin +TZD +

SU

DPP-4-i

GLP-1-RA

Insulin

or

or

or

SGLT2-ior

Metformin +DPP-4-I +

SU

TZD

Insulin

or

or

SGLT2-ior

Metformin +Insulin (basal) +

TZD

DPP-4-i

GLP-1-RA

or

orSGLT2-ior

Metformin +SGLT2-i +

SU

TZD

Insulin

or

orDPP-4-i

or

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Why Consider Insulin Early?The benefits of insulin

• The most predictable glucose reduction• Most effective.

• Effective targeting of fasting glucose• Also enhances post‐prandial insulin response as well

• Potential for preservation of beta cell function• Evidence of diabetes prevention in Origin Trial• Evidence of improved insulin secretion when added to oral agents

• Evidence of beta cell preservation/ prolonged remission when used early in T2DM

• Good safety record other than hypoglycemia• No evidence of increased cancer or heart disease with glargine in Origin Trial

ADA. Diabetes Care. 2015; 38 (suppl 1): S41‐S48;  Weng J, et al. Lancet. 2008;371:1753–60; Pennartz C, et al. Diabetes Care2011; 34:2048‐2053. ORIGIN Trial Investigators, Gerstein HC, et al. N Engl J Med. 2012;367(4):319‐28. 

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Early Insulin Increased Remission in Newly Diagnosed T2DM

CSII = continuous subcutaneous insulin infusion; MDI = multiple daily insulin injections; OHA = oral hypoglycemic agents.Weng J, et al. Lancet. 2008;371:1753‐60.

Target glycemic control was achieved in less time (4 & 5.6 days) and in more CSII and MDI pts (97.1% & 95.2%) than OHA pts (9.3 days and 83.5%)

Treatment was stoppedafter normoglycemia

was maintained for 2 weeks

Days in Remission

Perc

enta

ge o

f Pat

ient

s in

Rem

issio

n

40

60

100

00 450

20OHA (N=121)

36027018090

CSII (N=137)MDI (N=124)

80

27%

45%51%

p=0.0012

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Early Insulin in Newly Diagnosed T2DMImproves Insulin Secretion

β-Cell function was measured at the end of therapy and 1 year after.

Patients treated with continuous insulin therapy had an increase in activityof 160% compared to 105% for those treated with oral agents

*In the non‐remission group compared with that in each intervention in the remission group (after treatment). CSII = continuous subcutaneous insulin infusion; MDI = multiple daily insulin injections; OHA = oral hypoglycemic agents.  Weng J, et al. Lancet. 2008;371:1753‐60.

Acu

te In

sulin

Res

pons

e(p

mol

/L p

er m

in)

0

800

1200

1400

-200

400

600

1000

200

CSII in the Remission GroupMDI in the Remission GroupOHA in the Remission GroupNon-Remission Group

At 1 Year

P=0.006

p<0.0001

*p<0.05

After TherapyBefore Therapy

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Insulin Secretion Improvement After Basal Insulin is Added to Oral Agents

First Phase Insulin Secretion Second Phase Insulin Secretion

Pennartz C, et al. Diabetes Care.  2011; 34:2048‐2053.

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Basal Insulin Treatment in ORIGIN Trial‐ Safe and Effective for Diabetes Prevention ‐

HR PPrimary• CV death, MI, stroke  1.02 NS

• CV death, MI, stroke, revasc, CHF 1.04 NS

Secondary• All cause death 0.98 NS• Microvascular composite  0.97 NS• Progression of IFT or IGT to T2DM 0.72 0.006• Cancer 1.00 NS• All cause death 0.98 NS

Revasc = revascularization.The ORIGIN Trial Investigators. N Engl J Med. 2012; 367:319‐328.

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Riddle MC, et al. Diabetes. 2009;58(Suppl.1):A125.

A1C Reduction vs Baseline with Glargine

Pooled analysis of 2193 patients with 24 weeks titrated glargine added to OAD

No difference in hypoglycemia rates

-0.9

-1.4-1.6

-2.0

-2.6-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0A1c change from baseline

8.0-8.4Baseline A1c (%)

<8.0 8.5-8.9 9.0-9.4 ≥9.58.0-8.4Baseline A1c (%)

<8.0 8.5-8.9 9.0-9.4 ≥9.5

7563

5647

34

0

20

40

60

80

100% of patients attaining A1c <7%

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Hypoglycemia Reduced withBasal Insulin Analogs

Little S, et al. Diabetes Technol Ther. 2011:13(suppl 1):S53‐S64.

0

Hypo

glyc

emia

(eve

nts p

t-yr

-1)

6

10

2

A1C (%)

4

8

10.0

GlargineNPH

9.08.07.06.05.00

Hypo

glyc

emia

(eve

nts p

t-yr

-1)

2

12

14

4

A1C (%)

8

10.09.08.07.06.05.0

NPHDetemir

1

7

3

5

9

6

10

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Insulin Options In Type 2 Diabetes

• Basal only• Added to oral agents

• Basal plus• Adding one rapid acting analogs

sequentially starting with largest meal• Basal bolus

• Rapid acting analogs before each meal

• Pre-mixed

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When Basal Alone is Not Enough

When A1C values are still not at targetAND…

• Fasting BG levels at or approaching target• Post‐prandial BG values remain above target

Options:• Advance insulin therapy with additional prandial insulin• Add GLP‐1 agonist therapy if tolerated, not contraindicated and is affordable for the patient

BG = blood glucose.American Diabetes Association. Diabetes Care. 2015;38(suppl 1):S41‐S48.

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Glycemic Goal*

HbA1c, % <6.5 6.5 ‐ <7 7 ‐ <7.5 7.5 ‐ <8

FBG/premeal, mg/dL

<110  110‐125 126‐140 141‐160

AACE Algorithm for Starting Add‐on Insulin Therapy To Oral Agents or GLP1‐RA  

TDD: 0.1‐0.2 U/kg

Basal analog AM or PM (Less desirable NPH at HS)

Insulin titration every 2 – 3 days to reach glycemic goal*‐ Fixed regimen: Increase TDD by 2 U‐ Adjustable regimen:‐ FBG>180 mg/dl: add 4 U‐ FBG 140‐180 mg/dL: add 2 U‐ FBG 100‐139 mg/dL: add 1 U

HbA1C < 8% HbA1C  8% ‐ 10%

TDD: 0.3 U/kg

• Glycemic target ‐ HbA1c and FBG ‐ to be set‐up based on patients’ age, presence of co‐morbidities, diabetic complications, and hypoglycemia risk.

• For most patients a HbA1c < 7% and FBG < 130 mg/dL is recommended

Garber AJ, et al. Endocr Practice 2015;21:438‐447Endocr Practice 2015;21:1‐87

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ADA Recommendations For Advancing Insulin

ADA. Diabetes Care. 2015; 38 (suppl 1): S41‐S48.

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Comparative InsulinTrials in T2DMSummary of Key Findings With Basal Insulin

• Any insulin will lower glucose and A1C

• All insulins are associated with some weight gain and some risk of hypoglycemia

• The larger the doses and the more aggressive the titration, the lower the A1C, but often with a greater possibility of hypoglycemia

• Long‐acting insulin analogs reduce the incidence of overnight hypoglycemia

• Premixed insulin preparations are effective in reducing HbA1c but are associated with more hypoglycemia and weight gain than using individual short and long‐acting insulin

Inzucchi SE, et al. Diabetologia. 2012;55:1577‐96.

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Impediments to The Potential Benefit of Insulin Therapy in Type 2 Diabetes 

• Provider inertia• Delay in progression of therapy to reach target• Worse with insulin than other agents

• Behavioral barriers to initiating insulin• Patients• Providers

• Objective limitations once initiated• Non‐adherence• Hypoglycemia• Weight gain

Adapted from Funnell MM. Clinical Diabetes. 2007;25(1):36‐38. Derr RL, et al. Diabetes Spectrum. 2007; 20(3):177‐185.  Karter AJ, et al. Diabetes Care. 2010;33(4):733‐735.

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Patient Reported Reasons for Missing Insulin Injections

Grunberger G. Diabet Obes Metab. 2013;15(suppl 1):1‐5.

Years of US Survey50 1510 2520 3530

Need to plan daily activitiesaround injections

Often worry about hypoglycemia

Injections interfere witheating or exercise

Insulin injections negativelyaffect activities

Dread taking injections

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Overcoming the Barrier of Hypoglycemia with Insulin

• Less hypoglycemia with “basal only” approach• Analog insulins reduce hypoglycemia• Appropriate dosing reduces hypoglycemia• Choose the right target for each individual

• e.g. Higher targets for elderly or those with renal insufficiency

• Proper patient education is crucial• Learning to have consistent meals, adjust for exercise, monitor glucose, etc.

Morales J and Schneider D. Am J Med. 2014;127:S17‐24. American Diabetes Association. Diabetes Care. 2015;38 (suppl 1):S41‐S48.

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Hypoglycemia In 4T Trial At 1 Year‐ Higher rates with more complex regimens ‐

Holman RR et al. NEJM 2007;357:1716‐30  

5.7

12.0

2.3

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Characteristics of Available Basal Insulin Analogs

Benefits over NPH• Longer duration of action• Less variability • Less weight gain• Less hypoglycemia

Room for Improvement• More consistent 24+ hour coverage

• Flat time‐action profile• Less day‐to‐day variability• Less weight gain• Less hypoglycemia• More suppression of hepatic glucose production

Simon ACR. Diabetes Technol Ther. 2011;13(suppl 1):S103‐108.  Grunberger G. Diab Obes Metab. 2013;15(suppl 1):1‐5.

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The Evolution of Insulin Products

1922           1936           1946           1954           1977           1990s           2000s           2015‐ ‐

First Regular Insulin

Protamine Zinc Insulin 

(PZI) 

NPH Insulin

Lente Insulins

First Human Insulins

Rapid Acting Analogs

Prolonged Basal Insulin Analogs

ImprovedBasal Insulins Ahead 

Tibaldi JM. Am J Med. 2014;127:S25‐S38.

InhaledHumanInsulin

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Characteristics of the IdealBasal Insulin

• PD profile should be flat (peakless) • Low risk of hypoglycemia • Duration of action of 24 hours• Low variability within individual patients 

Arnolds S, et al. Int J Clin Pract. 2010;64(10):1415‐1424.

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Emerging Basal Insulins

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New and Investigational Basal Insulins

•U‐300 concentrated glargine –• approved 2015

•PEGylated insulin lispro• Insulin degludec

Garber AJ. Diabetes Obesity Metab 2013

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Recently Approved Basal InsulinHigh Concentration Glargine (U‐300)

• U‐300 insulin glargine offers a smaller depot surface area leading to a reduce rate of absorption

• Provides a flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency

• Half‐life is ~23 hours • Steady state in 4 days• Duration of action ≤36 hours• Associated with less hypoglycemia especially nocturnal

hypoglycemia• FDA approved February 2015• Is being evaluated as a fixed dose combination with lixisenatide

Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104‐19. Steinstraesser A, et al. Diabetes Obes Metab. 2014 Feb 26. [Epub ahead of print]. http://www.australianprescriber.com/magazine/19/3/76/8. Accessed March 11, 2014. http://www.medpagetoday.com/Endocrinology/Diabetes/46690. Accessed January.   

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Why Create Concentrated Insulin?• Impact of insulin concentration:

• Reduce volume for delivering insulin• Facilitates delivery of high dose insulin

• Changes the PK and PD of insulin

• Examples of concentrated insulin• U‐500 regular insulin

• Developed to treat highly insulin resistant diabetes• Does have longer action and delayed peak as well though this is a potential disadvantage for a short‐acting insulin

• U‐300 insulin glargine• Developed to prolong action and reduce variability of a long‐acting basal insulin – improved PK and PD

• The higher concentration may also hold benefits for insulin resistant patients but this is not the purpose or present use

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Pharmacodynamics ofU300 Glargine vs U100 Glargine

GIR = glucose infusion rateShiranoto M et al. Diab Obes Metab 2015;17:254‐60.

• The U-300 glargine has a flatter more prolonged effect • The time it takes for 50% of the effect of a single injection

– U-100 = 12.1 hours– U-300 = 16.7 hours

GIR

(mg/

kg-1

min

-1)*

1.5

3.0

00 36

Time (hours)3024126 18

0.5

2.5 U100 0.4 U/kg-1

U300 0.4 U/kg-12.0

1.0

U300 0.6 U/kg-1

U300 0.9 U/kg-1SC Injection

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Reduction in Documented Hypoglycemia With U300 Glargine vs U100 Glargine 

Added to Oral Agents in Type 2 Diabetes

Nocturnal ‐‐ RR 0.71 (0.58‐0.86)

Any Time of Day –RR 0.90 (0.83‐0.98)

Differences by time of day

Yki‐Yarvinen H, et al. Diabetes Care. 2014;37:3235‐43.

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U100 Glargine vs U300 Glargine in Type 2 Diabetes with Basal‐Bolus Regimen

Riddle MC et al. Diabetes Care. 2014;37:2755‐62. 

Lower rate of severe or confirmed hypoglycemia, particularly overnightTime period U100 U300 RR with U300 CI0-6 months Nocturnal 57.5% 44.6% 0.78 0.68 – 0.899 weeks – 6 mo Nocturnal 46.0% 36.1% 0.79 0.67 – 0.930-6 months 24 hours 87.8% 81.9% 0.93 0.89 – 1.04

Mea

n Hb

A1c

(%) 8.5

6.5Baseline Month 6

LOCFTimeMonth 6Week 12

8.0

U300U100

7.5

7.0

No difference inHbA1c change

Mean change in HbA1cfor both treatment groups

-0.83%

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Flexible vs Fixed Dosing U300 Glargine: Sub‐Studies of Phase III Trials

Ritzel R, et al. Presentation 919‐P 74th ADA Scientific Sessions June 13‐17, 2014, San Francisco, CA. http://ada.scientificposters.com/epsAbstractADA.cfm?id=6. Accessed August 15, 2014.

• No difference in A1C between flexible- vs fixed-dosing

• No difference in severe or nocturnal hypoglycemia within each sub-study

Edition 1 Sub-StudyN=109

Perc

enta

ge o

fIn

ject

ions

(%)

20

100

024 ±<1 h

80

60

40

24 ±1-3 h

24 ±>3 h

24 ±<1 h

24 ±1-3 h

24 ±>3 h

Edition 2 Sub-StudyN=89

Flexible DosingFixed Dosing

6 Months (randomization, sub-study)

U300 once dailyevery 24 ± 3h

U300 once dailyevery 24 h

9 Months (end of sub-study)

sub-study

6 Month Treatment Period(main study)

6 Month Extension Period(main study)

U300 once dailyevery 24 h

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U300 Glargine vs U100 Glargine in T2DM: Meta‐Analysis of Phase III Trials EDITION 1, 2, & 3

Baseline to Month 6RR (95% CI)Glar U300

(N=1247)Glar U100 (N=1249)

A1C (%), LS mean -1.02 -1.02 NS

Weight (kg), LS mean 0.49 0.75 P=0.058

Any hypo in 24 hr* 67.8 73.8 0.92 (0.87-0.96)

Any nocturnal hypo* 31.7 41.3 0.77 (0.69-0.85)

Confirmed BG <54 mg/dLor severe hypo* 26.9 33.3 0.81 (0.72-0.90)

Confirmed nocturnal BG<54 mg/dL or severe hypo* 9.7 13.2 0.73 (0.59-0.91)

*% people ≥1 event.LS = least squares; RR = relative risk; BG = blood glucose; CI = confidence interval.  Ritzel RA, et al. Presentation 963, 50th EASD Annual Meeting, September 15‐19, 2014, Vienna, Austria. 

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U‐300 Insulin Glargine

• Only available in pens

• 300 U/mL, 1.5 mL

• Max dose per shot is 80 units with 1 unit increments using current pen

• New pen in development will allow a max dose of 240 units

• U‐300 glargine pen is white and green with the concentration highlighted in orange to distinguish it from U‐100 glargine purple and gray

1. http://www.pdr.net/full‐prescribing‐information/toujeo?druglabelid=3688. Accessed March 26, 2015. 2. http://www.pdr.net/drug‐summary/lantus?druglabelid=520. Accessed March 26, 2015.

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U‐300 Insulin Glargine Dosing• Insulin‐Naive Patients:

• Type 1 Diabetes – Start with 1/3 to 1/2 of the total daily insulin dose calculated by using 0.2‐0.4 U/kg/day; give the remainder of the total daily insulin dose as a short‐acting insulin and divide between each daily meal

• Type 2 Diabetes – Start with 0.2 U/kg/day

• Type 1 or Type 2 Diabetes:

• Changing from once daily long‐acting or intermediate‐acting insulin:

• Initial dose can be the same as the once daily long‐acting dose; for patients controlled on U‐100 insulin glargine, expect that a higher daily dose of U‐300 glargine will be needed to maintain the same level of glycemic control

• Changing from twice daily NPH insulin:

• Initial dose is 80% of the total daily NPH dosage

http://www.pdr.net/drug‐summary/toujeo?druglabelid=3688. Accessed March 28, 2015.

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Use of U‐300 Glargine vs U‐100 Glargine

• There are no specific FDA guided instructions on which glargine formulation should be used first

• U‐300 and U‐300 results in similar improvement in glycemic control

• U‐300 appears to have the lowest rate of hypoglycemia

• The difference in hypoglycemia and duration of action is likely to have a greater impact in type 1 DM 

• No published experience with U‐300 in the hospital where the longer duration of action is less likely to carry an advantage

• For example, it is recommended that U‐300 insulin should be adjusted only every 3‐4 days

• Switching from U‐100 to U‐300 is likely to require up‐titration

Toejeo Package Insert

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When Might U‐300 Glargine Be Considered?

• Patient concerned about hypoglycemia• Patient experiencing nocturnal hypoglycemia with current basal insulins

• Patient on current basal insulins not lasting throughout the day

• Patient wanting basal insulin with the lowest risk of hypoglycemia

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Basal Insulins in DevelopmentPEGylated Insulin Lispro*

• Polyethylene glycol polymer covalently attached to lispro

• Half‐life 2‐3 days• Steady state in 7‐10 days• Duration of action >36 hours• Evidence of some hepatic specificity

• Uncertain significance of liver enzyme elevations

• Evidence for weight benefit• Phase III studies ongoing

*Not FDA approvedGarber AJ. Diabetes Obesity Metab. 2014;16:483‐91. Owens DR, et al. Diabetes Metab Res Rev. 2014; 30(2):104‐19. Sinha VP, et al. Diabetes Obesity Metab. 2014;16(4):344‐350. Bergenstal RM, et al. Diabetes Care 2012;35:2140‐47. 

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Pharmacodynamics of PEGylated Insulin Lispro (LY2605541)After First Dose and 14th Dose

GIR = glucose infusion rate.Sinha VP, et al. Diabetes Obesity Metab. 2014;16(4):344‐350.

DAY 1Glucose Infusion Rate

DAY 14Glucose Infusion Rate

0

GIR

(mg/

kg/m

in)

5.0

0

1.0

Time (hours)

4.0

2420161284 2218141062

2.0

3.0

3.0 nmol/kg (0.33 U/kg)4.5 nmol/kg (0.50 U/kg)6.0 nmol/kg (0.67 U/kg)9.0 nmol/kg (1.00 U/kg)

0

GIR

(mg/

kg/m

in)

5.0

0

1.0

Time (hours)

4.0

2420161284 2218141062

2.0

3.0

3.0 nmol/kg (0.33 U/kg)4.5 nmol/kg (0.50 U/kg)6.0 nmol/kg (0.67 U/kg)9.0 nmol/kg (1.00 U/kg)

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LY2605541 vs U100 Glargine In Type 2 Diabetes as Measured with CGM

Reduced Variability (SD) Reduced Hypoglycemia

Bergenstal RM et al. Diabetes Care 2014;37:659‐65

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PEGylated Insulin Lispro (LY2605541) vs Glargine U100 in T1DM

Rosenstock J, et al. Diabetes Care. 2013;36(3):522‐528.

LY2605541 Treatment at 8 wks• Significantly lowered A1C vs glargine

• Significantly reduced weight (1.2 kg)

• Increased overall hypos (P=0.04) but less nocturnal hypos (p=0.01)

• Lowered prandial insulin dose

• Significantly increased liver enzymes

7.4

7.6

7.0

7.8

7.2

8.0

0

A1C

(%)

Treatment Period 1

6.8

88

83

0

Wei

ght (

kg)

0 4Week

128

80

16

Treatment Period 2(Crossover)

85

87

82

86

81

84

LY2605541Glargine 

P<0.001

P<0.0001

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Basal Insulins in DevelopmentInsulin degludec*

• desB30 insulin acylated (16 carbon fatty acid chain) at LysB29 

• Duration of action >42 hours• Half‐life ~25 hours

• Detectable for at least 5 days• Steady state in 2‐3 days• FDA denied approval in 2013, research continues to confirm cardiovascular safety

• DEVOTE Trial ongoing• Is being evaluated in fixed combination with liraglutide ‐ ‐ results show added benefit vs single agent

*Not FDA approvedGarber AJ. Diabetes Obesity Metab. 2014;16:483‐91Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104‐19

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Pharmacodynamics of Degludec

Josse RG and Woo V. Diabetes Obes Metab. 2013;15(12):1077‐1084.

Glucose Low

ering Effect

on Day 6 (m

g/kg/m

in)

2

6

00 24

Time since Injection (hours)201684 12

4

1

3

5Degludec 0.4 U/kg

Degludec 0.8 U/kgDegludec 0.6 U/kg

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Degludec vs U100 Glargine In Type 2 DMEqual Efficacy, Less Nocturnal Hypoglycemia and Less Overall Documented 

Hypoglycemia with Degludec

Garber AJ, et al. Lancet. 2012;379(9285):1498‐1507.

2.0

1.0

0

Cum

ulat

ive

Even

tspe

r Par

ticip

ant

0 16Time (weeks)

4028

0.2

52

1.4

1.8

0.8

1.6

0.6

1.2

0.4

4 3220 4412 3624 488

14

10

0

Cum

ulat

ive

Even

tspe

r Par

ticip

ant

0 16Time (weeks)

4028

2

52

8

6

12

4

4 3220 4412 3624 488

0 16 4028 524 3220 4412 3624 488

8.6

7.8

0

A1C

(%)

7.0

8.28.4

7.67.4

8.0

7.2

70

62

0

A1C

(mm

ol/mol)

54

6668

6058

64

56

Insulin Degludec once-daily (N=744)Insulin Glargine once-daily (N=248)

Time (weeks)

Nocturnal  Confirmed Hypoglycemiap = 0.04

Cumulative Hypoglycemia per Participant per 24 hoursp= 0.036

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Hypoglycemia: Degludec vs. Glargine

NOCTURNAL

Ratner R, et al. Diabetes, Obesity and Metabolism 2013;15:175

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Hypoglycemia Ratio: Ideg vs. IglargMetaanalysis

N(ideg)

N(glarg)

Day‐time (full)

Nighttime (full)

Day‐time (Maint)

Night‐time (Maint)

T1DB/B 637 321 1.14 0.83* 1.06 0.75*T2DB 1,290 632 0.89 0.64* 0.80* 0.51*T2DB/B 753 251 0.83* 0.75* 0.84 0.71*

Vora et al. Diabetes Ther 2014: DOI 10.1007/s13300‐014‐0076‐9 * Significant based on 95% CI

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Hypoglycemia Age 65+: Ideg vs Iglarg Metaanalysis

Sorli et al. Drugs Aging (2013) 30:1009–1018 * Significant based on 95% CI

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Head‐To‐Head Trials of Basal Insulin Products:Aim to Reduce Hypoglycemia

HbA1c Overall Hypo Nocturnal Hypo Other

Glargine vs NPH Similar Decreased Decreased

Detimer vs NPH Similar Decreased Decreased

Glargine vs Detimer Similar Similar Similar Det – lower weightGlar – lower dose ?

Degludec vs Glargine U100 Similar Decreased or same

Decreased

U300 vs U100 Glargine w B‐B

Similar Decreased * Decreased*

U300 vs U100 Glargine, basal  only

Similar + / ‐ * Decreased *

PEGylated Lispro vs Glargine

Lower? +/ ‐ Decreased PEGL ‐‐ Lower weight

* designates severe and documented hypoglycemia but some variance by early vs later parts of the studyTibaldi JM, et al.  Am J Med 2014; 127:S25‐S38.  Riddle MC, et al. Diab Care  2014; 37:2755‐2762.  Yki‐Jarvinen H, et al.  Diabetes Care. 2014 37:3225‐3243.  Rosenstock J, et al.  Diabetes Care. 2013; 36:522‐528.               

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Summary• T2DM is marked by progressive beta cell dysfunction requiring progressive pharmacological therapy to maintain glucose control

• Available guidelines promote stepwise advancement of therapy that includes basal insulin as an option after metformin

• Insulin regimens should be tailored to the patient’s preferences and needs taking into consideration the pros and cons of each regimen

• The real and the perceived threat of hypoglycemia are major barriers among the multiple barriers to appropriately advancing therapy

• New basal insulins in development appear to offer further advantages in more consistent 24 hour coverage, reduced hypoglycemia and possibly weight advantage