3/11/19

1

Next Generation Diabetes Management: Titratable Fixed-Ratio Combination Therapy with Basal

Insulin/GLP-1 RA to Better Manage Type 2 Diabetes

Supported by an educational grant from Sanofi US

Faculty Disclosure

Angela Thompson, DNP, FNP-C, BC-ADM, CDE, FAANP

No relevant financial relationships to disclose

2

Please complete the first 2 pages of the assessment form now

3

tiny.cc/dmTNP

Go here to complete assessment online (and save a tree)

4

CASE sensitive

Learning ObjectivesØ Compare and contrast current guidelines/recommendations for patients with type 2

diabetes mellitus (T2DM) not at goal

Ø Review data on combination GLP-1 RAs and basal insulin for individuals with T2DM when intensification is needed

Ø Identify how fixed-dose combination therapy with GLP1-RA and insulin can help patients achieve glycemic goals

Ø Formulate strategies to overcome barriers to the introduction and intensification of fixed ratio therapies

WWW.AANP.ORG 5

CURRENT STATE OF GLYCEMIC CONTROL AND REVIEW OF UPDATED T2D GUIDELINES

WWW.AANP.ORG 6

3/11/19

2

T2D: A Global Epidemic• T2D global prevalence = 424.9 million peopleo 30.3 million people have diabetes / 9.4% of the US population (2017)o 7th leading cause of death in the US o Projected to be 628.6 million in the year 2045

• Considerable economic cost: Total US diabetes healthcare expenditures = $727 billion (2017)

WWW.AANP.ORG 7

Complications of T2DM can be delayed and possibly avoided with timely and aggressive treatment with lifestyle modification, medication, and follow-up

http://www.who.int/diabetes/en/. Accessed 2.28.18 https://www.cdc.gov/diabetes/prevention/index.html,

Current Recommendations

AACE ADAA1C (%) ≤6.5 ≤7

Pre-prandial mg/dL <110 80-130

Peak postprandial mg/dL <140 <180

WWW.AANP.ORG 8

Endocr Pract.2018,doi:10.4158/CS-2017-0153.

Diabetes Care Volume 41, Supplement 1, January 2018.

Reprinted with permission from American Association of Clinical Endocrinologists © 2018 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2018. Endocr Pract.2018;24: 91-120. Reprinted with permission from American Association of Clinical Endocrinologists © 2018 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2018. Endocr Pract.2018;24: 91-120.

Combination Injectable Therapy for T2D

11

American Diabetes Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), 2018. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association

Clinical Case

WWW.AANP.ORG 12

3/11/19

3

64 year old Male with T2DM

WWW.AANP.ORG 13

Medical history

MI/CABG x2 - 2007

Stent x2 – 2008

Diabetes dx 2008

Hypertension – well

controlled on medication

Hyperlipidemia – well

controlled on medication

November 2017 Visit

A1C 12.9%

Quit his GLP1-RA 4 months

ago (A1C was 7.8% at that

time)

Not feeling well lately and

very surprised at his lab

results today

Restarted his GLP1-RA after

today’s visit

June 2018 Visit

A1C 9%

6 months later his A1C is

down and he is still taking his

GLP1-RA.

Not at goal

14

Patient Perspective: Mark’s Story

Rationale for a Fixed-Ratio CombinationHow could a GLP-1 RA and Basal Insulin help Mark get to goal?

WWW.AANP.ORG 15

Incretin Response to Insulin Secretion

WWW.AANP.ORG 16

Oral glucose loadIntravenous glucose infusion

Time (min)

Insu

lin (m

U/l)

80

60

40

20

018060 1200

Time (min)

Insu

lin (m

U/l)

80

60

40

20

018060 1200

Incretineffect

Control subjects (n=8) Persons with T2D (n=14)

A dap ted by pe rm ission from S pringer-V erlag : S p ringer N a tu re D iabe to log ia . R educed inc re tin e ffec t in T ype 2 (non-in su lin -dependen t) d iabe tes, M . N auck , F . S tO ckm ann , R . E bert and W . C reu tz fe ld t, C O P Y R IG H T (1986)

Springer Nature

Physiologic Effect of Glucagon-Like Peptides (GLP)

WWW.AANP.ORG 17

Glucagon reduces hepatic glucose output

Promotes satiety & reduces appetite

Alpha cells:↓Postprandial

glucagon secretion

Beta cells:G lucose-dependent

insulin secretionGLP1 secreted when food ingested

Slows gastric emptying

GLP-1 RA + Basal Insulin: RationaleCharacteristic GLP-1 RA Basal Insulin

MOA(Mechanism of Action)

Óglucose-dependent pancreatic insulin secretionÔglucose-dependent glucagon secretionÔgastric emptyingÓsatiety/↓appetite

Mimics basal rate of endogenous insulinÓglucose disposalÔhepatic glucose production

Glucose profile Short-acting agents: ÔPPG excursionsLong-acting agents: ÔPPG + FPGÔ A1C 0.9 - 1.6%

ÔFPG

Body weight ÔWeight ÓWeightEffect on pancreatic ß cells

May improve ß cell function Rests ß cellsÔglucose toxicity

WWW.AANP.ORG 18

Anderson SL, Trujillo JM. Diabetes Spectrum. 2016; 29:152-160. Vedtofte L, et al. Exper Rev Clin Pharmacol. 2015;8:273-282.

3/11/19

4

GLP-1 RA + Basal Insulin (cont.)Characteristic GLP-1 RA Basal Insulin

Contraindications • eGFR<30 (exenatide)• Gastroparesis, pancreatitis,

acute gall bladder disease• Black box: contraindicated with

personal/family history MTC* or MEN2# (except exenatide)

Side Effects • Nausea • Diarrhea• Vomiting

• Hypoglycemia• Weight gain

WWW.AANP.ORG 19

Anderson SL, Trujillo JM. Diabetes Spectrum. 2016; 29:152-160. Vedtofte L, et al. Exper Rev Clin Pharmacol. 2015;8:273-282.

*MTC :Meducillary thyroid carcinoma; # MEN2: Multiple endocrine neoplasia type 2

GLP-1 RA + Basal Insulin Fixed-dose Combination AgentsIDegLira (Xultophy)− Insulin degludec (100 U/mL)−Liraglutide (3.6 mg/L)

LixiLan (Soliqua)− Insulin glargine (100 U/mL)−Lixisenatide (33 mcg/mL)

WWW.AANP.ORG 20

GLP-1 RAs in Fixed-dose CombinationsProperty Liraglutide LixisenatideHalf-life, hours 12.6 2 – 3

A1C change, % –0.6 to –0.9* –0.7 to –0.9

Body weight change, kg –1.8 to –3.0 –1.6 to –3.8

Nausea, % of patients 11.3 to 31.0 26.0 to 43.5

Hypoglycemia, % of patients 4.1 to 12.0 3.7 to 7.2

WWW.AANP.ORG 21

*Degree of change depended on study design and dose (1.2 or 1.8 mg)

Courtney H, et al. Diab Metabolic Synd Obes: Targets Ther. 2017;10:79-87

Combined Insulin and GLP-1 RA:IDegLira vs Max Liraglutide or Exenatide

WWW.AANP.ORG 22

Change in A1C (%) Change in BWt (kg)

Lin jaw i, S ., B ode , B .W ., C hayk in , L .B . e t a l. D iabe tes T her (2017) 8 : 101 . h ttps ://do i.o rg /10 .1007 /s13300-016-0218-3 .

Combined Insulin + GLP-1 RA: IDegLira vs Insulin Glargine up-Titration

WWW.AANP.ORG 23

Insulin glargine Insulin degludec/liraglutide Reproduced with permission from JAMA. 2016. 305(9): 898-907. Copyright© (2016) American Medical Association. All rights reserved

Combined Insulin and GLP-1 RA: LixiLan

WWW.AANP.ORG 23

American Diabetes Association Benefits of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide,

Versus Insulin Glargine and Lixisenatide Monocomponents in Type 2 Diabetes Inadequately Controlled on Oral Agents: The LixiLan-O Randomized Trial, 2016. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association

3/11/19

5

Practical Considerations in Patient Selection

WWW.AANP.ORG 25

Using Combination Basal Insulin/GLP-1 RAName Strength Indication/DosingDegludec/liraglutide combination (Xultophy®)

100/3.6

Maximum daily dose50 units

• For use if basal insulin <50 units daily or liraglutide < 1.8mg daily

• Administered daily/ same time • Starting dose 16 units/0.58 mg

(each 1 unit increment=0.4 mg)Glargine/lixisenatide combination(Soliqua®)

100 /33

Maximum daily dose 60 units

• Administer daily 1 hour before 1st

meal of day• Starting dose 15 units/5 mg if

taking glargine <30 units (1unit= 0.4 mg)

• Starting dose 30 units/10 mg if taking 30-60 units of glargine

WWW.AANP.ORG 26

Degludec/Liraglutide (Xultophy®)Xultophy Degludec Liraglutide Xultophy Degludec Liraglutide16 16 units 0.58 mcg 34 34 units 1.22 mcg18 18 units 0.65 mcg 36 36 units 1.3 mcg20 20 units 0.72 mcg 38 38 units 1.37 mcg22 22 units 0.79 mcg 40 40 units 1.44 mcg24 24 units 0.86 mcg 42 42 units 1.51 mcg26 26 units 0.94 mcg 44 44 units 1.66 mcg28 28 units 1.01 mcg 46 46 units 16.7 mcg30 30 units 1.08 mcg 48 48 units 1.73 mcg32 32 units 1.15 mcg 50 50 units 1.8 mcg

WWW.AANP.ORG 27

Glargine/Lixisenatide (Soliqua®)Soliqua Lantus Lixisenatide Soliqua Lantus Lixisenatide15 15 units 5 mcg 38 38 units 12.7 mcg18 18 units 6 mcg 40 40 units 13.3 mcg20 20 units 6.7 mcg 42 42 units 14 mcg22 22 units 7.3 mcg 44 44 units 14.7 mcg24 24 units 8 mcg 46 46 units 15.3 mcg26 26 units 8.7 mcg 48 48 units 16 mcg28 28 units 9.3 mcg 50 50 units 16.7 mcg30 30 units 10 mcg 52 52 units 17.3 mcg32 32 units 10.7 mcg 54 54 units 18 mcg34 34 units 11.3 mcg 56 56 units 18.7 mcg36 36 units 12 mcg 60 60 units 20 mcg

WWW.AANP.ORG 28

Dose Adjustment: Degludec/Liraglutide (Xultophy®) and Glargine/Lixisenatide (Soliqua ®)

WWW.AANP.ORG 29

Instruct on Needle Size and Safety

• Demonstrate pen use with a demo, OR• Take first injection in the office• Site preparation and rotation• Unopened and opened storage recommendations• Safely disposal of needles

WWW.AANP.ORG 30

Image by BruceBlaus [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from W ikimedia Squares

3/11/19

6

Individualizing a T2D Management Approach

A Age

B Body weightBlood pressure management

C Complications

D Duration of diabetes/Determine treatment goals

WWW.AANP.ORG 31

E Expense/life expectancy

F Feelings/attitudes

G Glycemic targets

H Hypo/Hyperglycemic concerns

Adapted from: https://www.cdc.gov/diabetes/ndep/pdfs/ppod-guide-team-care-approach.pdf

32

Patient Perspective: Individual Approach

Patient-Centered Communication Recommendations

WWW.AANP.ORG 33

Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S28-S37

Use person-centered; focus

on patient strengths

Elicits patient preferences and

beliefs

Uses active listening skills

Assesses literacy, numeracy, and

potential barriers to care

Optimizes patient health outcomes

and health-related quality of life

CASE STUDY- MARK

WWW.AANP.ORG 34

Medical historyAge 52BMI- 32, wt. 208 lbs.BP 134/70A1c 9%

Medications:Injecting liraglutide 1.8 mg dailyMetformin 500mg XR 2 tabs daily in eveningAtorvastatin 40mg dailyLisinopril 20mg daily

Daily Glucose LogDay of the Week

Fasting Dinner

Monday 287

Tuesday 155 211

Wednesday 200 199

Thursday 212

Friday 149 184

Saturday 233

Treatment Plan

• To continue metformin• Stop liraglutide 1.8 mg

daily• To start fixed-ratio

combination injection at starting dose

• To increase dose by 4 units every week until average fasting less than 130

Formulating Strategies to Overcome Barriers to Introduction and Intensification of Fixed-Ratio Therapies

WWW.AANP.ORG 35

Common Nurse Practitioner (NP) Barriers to Treatment Intensification

• Uncertainty about A1C goals and guidelines

• Lack of training about how to intensify antihyperglycemic therapy

• Unawareness of new treatment/medication options

• Time constraints

• Lack of care coordination

• Patient motivation, including fears and concerns with dosing regimen

WWW.AANP.ORG 36

https://doi.org/10.1016/j.Diabets.2011.02.002

Blonde, 2017, Quality in Primary Care (2017) 25 (3): 176-186

3/11/19

7

Strategies to Guide T2DTreatment Intensification: From the NP Perspective

Prioritize Prioritize goals & set realistic goals

Follow upRegular follow- up appointments- longer time & shorter intervals

SolicitFeedback

Elicit patient feedback, be open minded

UtilizeAvailable patient education resources-AANP, ADA, AADE

DevelopNon-judgmental approach- avoiding blame and shame

ReferAs appropriate to other healthcare disciplines- diabetes educators, specialists

37

Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S28-S37

WWW.AANP.ORG 38

Patient Perspective: Communication

Strategies to Help Overcome Patient Barriers to Treatment

Determine Barriers• Needle size/fear of injections?• Dose complexity, need for

mixing solutions, cumbersome devices (vial and syringe)?

• Misconceptions/myths?• Fear of medication classes?• Side effect concerns: weight

gain, hypoglycemia?

WWW.AANP.ORG 39

Highlight Solutions• Smaller needle size options• Ease of therapy• Dose simplicity• Weight loss• Reduced hunger• Glycemic stability

Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S28-S37

CASE STUDY- MARK

WWW.AANP.ORG 40

Medical history

Age 52BMI- 31, wt. 206BP 127/84Current A1c 7.2%

Medications:Fixed-ratio combination injection 28 units dailyMetformin 500mg XR 2 tabs daily Atorvastatin 40mg dailyLisinopril 20mg daily

Daily Glucose LogDay of the Week Fasting Dinner

Monday 133 201

Tuesday 115 111

Wednesday 101 159

Thursday Forgot to test

Friday 177 184

Saturday 142 No test

Treatment Plan

• No side effects or hypoglycemia

• Average fasting 108 at 28 units of fixed-ratio

combination

• Encouraged continue weight loss and lifestyle

Conclusion• Effective management of diabetes is a multifaceted and includes an

individualized treatment regimen based on attributes from the acronym A-H (age, body weight, complications, duration of diabetes, etc.)

• Fixed- dose combination therapy targets multiple pathophysiological defects in Type 2 diabetes while conferring improved glucose control with low risk for hypoglycemia

• Less complex treatment regimens such as fixed-dose combinations promote greater patient adherence

• A patient centered approach with shared decision can help address the patient barriers to intensification along with proper patient education & resources

WWW.AANP.ORG 41 42

Please complete and turn in your posttest and evaluation!