A partnership of the Healthcare Association of New York State and the Greater New York Hospital Association

Glycemic Control Coaching Call

June 21, 2016

NYS PARTNERSHIP FOR PATIENTS

Agenda

2

Topic Speaker

Welcome and Introduction Cathleen Wright NYSPFP

Outpatient DM Medication

Thérèse Franco, MD, FHM Virginia Mason Medical Center

Seattle, WA

Naina Sinha, MD Assistant Professor of Medicine

Division of Endocrinology, Diabetes & Metabolism Weill Cornell Medical College

New York, NY

Next Steps and Q&A Alissa Beers NYSPFP

NYS PARTNERSHIP FOR PATIENTS

Glycemic Management Resources

3

o Webinar 4- September 13, 2015 from 12 – 1 pm

o Society for Hospital Medicine Glycemic ControlCommunity

o NYSPFP Project Manager

o NYSPFP Website

NYS PARTNERSHIP FOR PATIENTS

Glycemic Control Conference Agenda

July 22, 2016 4

Topic Presenter

Improving Glycemic Control in Non-Critical Care Units

Society for Hospital Medicine Faculty

Improving Glycemic Control in Critical Care Units

Hardwiring Glycemic Control Practices

Special Situations

Hypoglycemia Society for Hospital Medicine Faculty

Role of Glycemic Control Program in the Hospital

Transition out of the Hospital

Patient and Professional Education

NYS PARTNERSHIP FOR PATIENTS

Questions for Audience

5

o What have you implemented since attending thein-person Glycemic Control conference?

o What, if any, challenges are you experiencing inimplementing changes to your GlycemicManagement Program/protocols?

o What, if any, questions do you have relative tothe Glycemic Control conference topics?

6

Outpatient DM Medication

Advancing Glycemic Control in an Inpatient Setting

7

Presenters

Thérèse Franco, MD, FHM Virginia Mason Medical Center Seattle, WA

Naina Sinha, MD Assistant Professor of Medicine Division of Endocrinology, Diabetes & Metabolism Weill Cornell Medical College New York, NY

8

Type 1 vs Type 2 Diabetes

Type 1 • Autoimmune disease• β-cell destruction

• Little or no insulinproduction

• Ketosis prone

Treatment: • Lifestyle Changes• Insulin Dependence

Type 2 • Insulin resistance &• Insulin deficiency &• Gut hormone GLP-1

deficiency & GIP resistance

• weight, BP & LDLcommon

Treatment: • Lifestyle Changes• Oral agents, GLP-1 RAs• May Require insulin

9

Glu

cose

(m

g/dL

)

Diabetes diagnosis

50

100

150

200

250

300

350

Fasting glucose

Kendall DM, Cuddihy, RM, Bergenstal RM © 2009 International Diabetes Center. All rights reserved

Years

Rel

ativ

e am

ount

-10 -5 0 5 10 15 20 25 30

Insulin resistance

Insulin level

Onset Diabetes

Pre Diabetes (IFG, IGT)

0

50

100

150

200

250

-15

Natural History of T2DM

Postmeal Glucose

10

peripheral glucose uptake

hepatic glucose production

pancreatic insulin secretion

pancreatic glucagon secretion

Multiple Defects of T2DM

HYPERGLYCEMIA

− +

−

gut carbohydrate delivery & absorption

incretin effect

?

Renal Threshold

11

Diabetes Med Timeline, US.

12

Targeted Sites of T2DM Meds ↑Insulin

SUs Meglitinides GLP-1, DPP-4 I

GLP-1, Amylin TZDs, Metformin

↓Glucagon

GLP-1, DPP-4 I Amylin

TZDs

SGLT-2 inhibitors

Metformin GLP1, TZDs

GLP-1, Amylin, AGIs

Defronzo RA. Diabetes;2009;58:773-795

↓HGP

↑Glu uptake

↓Glu reabsorption

Gl effects CNS effects

↓Lipotoxicity

Tahrani. AA. Lancet. 2011; 378:182-97

13

Glycemic Targets- ADA/EASD 2016 • HbA1c < 7.0% (mean PG ∼150-160 mg/dl)

Pre-prandial PG 80-130 mg/dl

Peak post-prandial PG <180 mg/dl

• Individualization is key:

Tighter targets (6.0 - 6.5%) - younger, healthier

Looser targets (7.5 - 8.0%+) - older, co-morbidities, hypoglycemia prone, etc.

• Avoidance of hypoglycemiaDiabetes Care 39: S43-44

14

Factors to Consider when Choosing Pharmacological Agents for Diabetes ►Current A1C

►Duration of diabetes

►Body weight (BMI, abdominal obesity)

►Age of patient

►Co-morbidities

►Risk of hypoglycemia

►Cost of medication

►Convenience/ complexity

15

Biguanides

• Metformin (Glucophage®)• Metformin XR (Glucophage XR®, Fortamet®,

Glumetza®)• Metformin liquid (Riomet®)

16

Biguanides Metformin Mechanism ↓ hepatic glucose production

↑ insulin sensitivity Efficacy ↓ A1c 1.5%

Advantages ↓ CV risk (UKPDS), ↓ IGT -> T2DM (DPP) no hypos ↓ appetite- possible wt loss ↓ cancer risk $ generic

Disadvantages GI s/e Lactic acidosis (very rare) B12 def

Contraindications Impaired renal fx (eGFR <30) excessive ETOH, CHF Hold 48 hrs pre/post contrast studies Caution in elderly (>80 yo)

17

Thiazolidinediones (TZD’S)

• Pioglitazone (Actos®)• Rosiglitazone (Avandia®)

18

TZDs Pioglitazone, Rosiglitazone

Mechanism ↑ Insulin sensitivity- ↓ resistance

Efficacy ↓ A1c 0.8-1.0% Advantages No hypos; durable

No renal excretion Beneficial lipid effects; + vasc effects (pio) ↓ insulin requirement

Disadvantages Slow onset Wt gain –sc, peripheral Fluid retention/edema- esp w/insulin Bladder CA risk- pio (?) Macular edema; fracture risk

Contraindications Black box-> may cause/exacerbate CHF; contraindicated NYHA Class III or IV CHF

19

Sulfonylureas

• Glimepiride (Amaryl®)• Glipizide (Glucotrol®, Glucotrol XL®)• Glyburide (Micronase®, Glynase®, DiaBeta®)

20

Sulfonylureas Glimepiride, Glipizide, Glyburide

Mechanism ↑ insulin secretion- long acting (12-24 hrs) - need functioning beta cells

Efficacy ↓ A1c 1-2% Advantages No lag time

Easy dosing $

Disadvantages Hypos (esp glyburide) Wt gain Low durability

Contraindications Caution if renal/hepatic disease Adjust dose in elderly Sulfa allergy

21

Glinides

• Repaglinide (Prandin®) - meglitinide• Nateglinide (Starlix®) - amino acid derivative

22

Glinides Repaglinide, Nateglinide

Mechanism ↑ insulin secretion- fast acting , short duration (onset 15-30 min; lasts 2-4 hrs) - need functioning beta cells ↓ PPG

Efficacy ↓ A1c 1- 1.5% Advantages Work quickly; short half life

Can titrate based on BG, carb content Safe at higher levels of Cr than SUs

Disadvantages Hypos, wt gain (less than SUs) Frequent dosing

Contraindications Caution if renal/hepatic disease Adjust dose in elderly

23

Alpha-glucosidase Inhibitors

• Acarbose (Precose®)• Miglitol (Glyset®)

24

AGIs Acarbose, Miglitol

Mechanism Delays CHO absorption in small intestine ↓ PPG

Efficacy ↓ A1c 0.5- 0.8%

Advantages no wt gain no hypos Non-systemic- good CV safety

Disadvantages Flatulence, bloating, diarrhea Frequent dosing- with meals If used with insulin/secretogogue-> must treat hypos with glucose Limited efficacy

Contraindications Intestinal disorder Cirrhosis

25

Incretins- key points:

• GLP-1 and GIP- major incretin (gut) hormones• Involved in many aspects of glu metabolism• Effect diminished in T2DM• Released in response to food ingestion• Degraded by DPP-4• Possible β-cell preservation

26

GLP-1 Effects in Humans

Stomach: Helps regulate

gastric emptying

Promotes satiety and reduces appetite

Liver: ↓ Glucagon reduces

hepatic glucose output Beta cells: Enhances glucose-dependent

insulin secretion

Alpha cells: ↓ Postprandial

glucagon secretion

Secreted upon the ingestion of food

27

Nauck et al. Diabetologia. 1986

Incretin effect on insulin secretion

Oral glucose load Intravenous glucose infusion

Time (min) In

sulin

(mU

/l)

80

60

40

20

0 180 60 120 0

Time (min)

Insu

lin (m

U/l

)

80

60

40

20

0 180 60 120 0

Incretin effect

Control subjects (n=8) People with Type 2 diabetes (n=14)

28

GLP-1 enhancement GLP-1 secretion is impaired in T2DM

Natural GLP-1 has extremely short half-life

Add GLP-1 agonists with longer half-life: • exenatide• exenatide LAR• liraglutide• albiglutide• dulaglutide

Injectables

Block DPP-4, the enzyme that degrades GLP-1: • sitagliptin• saxagliptin• linagliptin• alogliptin

Oral agents

29

GLP-1 Receptor Agonists Exenatide (Byetta®)

Exenatide LAR (Budureon®)

Liraglutide (Victoza®)

Albiglutide (Tanzeum ®)

Dulaglutide (Trulicity®)

30

GLP-1 RA • Advantages

– Appetite suppression, wt loss– Glucose dependent insulin secretion– Low risk of hypos– Dosing- some weekly– CV benefit (Liraglutide- LEADER trial, 2016)

• Disadvantages/caution– s/e: nausea– Pancreatitis– Renal disease; contradindicated eGFR<30 (exenatide)– Gastroparesis– Black box: risk of MTC (medullary thyroid CA)– $$$

31

Exenatide (Byetta®) Exenatide LAR (Bydureon®)

• Exenatide- FDA -> 2005Exenatide LAR- FDA -> 2012

• Synthetic GLP-1 (53% homology)

32

Exenatide /Exenatide LAR

Exenatide- • monotherapy and w/metformin, TZD, SU, basal

insulin• Dose: 5 or 10 mcg SC bid within 60min of meal

Exenatide LAR • w/metformin, TZD, SU• Dose: 2 mg SC weekly independent of meals

33

Liraglutide (Victoza®)

• FDA -> 2010• Analog of human GLP-1 (97% homology)• monotherapy and w/ metformin, TZD, SU, basal

insulin• Once daily, independent of meals• Dose: start 0.6mg SC qd x1wk, then 1.2 mg; can

titrate to 1.8 mg• Saxenda® - FDA-> 12/14; wt loss; 3 mg/day• IDegLira – insulin degludec + liraglutide

34

Other GLP-1 RA

Albiglutide (Tanzeum®) • FDA-> 4/14• Dose: 30 mg or 50 mg weekly• Mixing, wait required• OK w/ basal insulin

Dulaglutide (Trulicity®) • FDA-> 9/14• Dose: 0.75 mg or 1.5 mg weekly• Autoinjector

35

GLP-1 RA Drug Dose Dosing

schedule Mixing Needles

Byetta® (exenatide)

5 mcg 10 mcg

Twice daily within 60 min of meal

No Not included (32 g 4mm)

Bydureon® (exenatide LAR)

2 mg Weekly Yes 23 g, 7 mm

Tanzeum® (albiglutide)

30 mg 50 mg

Weekly Yes 29 g, 5 mm

Trulicity® (dulaglutide)

0.75 mg 1.5 mg

Weekly No 29 g, 5 mm Built in

Victoza® (liraglutide)

0.6, 1.2, 1.8 mg

Daily No Not included (32 g 4 mm)

36

Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876-913 Deacon CF et al. Diabetes. 1995;44:1126-1131

DPP-4 Inhibitors

GLP-1 actions

Mixed meal

GLP-1 active

Plasma

Intestinal GLP-1 release

GLP-1 inactive

DPP-IV

Rapid inactivation (>80% of pool)

Renal clearance

X

37

DPP- 4 inhibitors

• Sitagliptin (Januvia®) – FDA->10/06• Saxagliptin (Onglyza®) - FDA -> 7/09• Linagliptin (Tradjenta®) - FDA -> 5/11• Alogliptin (Nesina®) – FDA-> 1/13

38

DPP-4 Inhibitors Sitagliptin, Saxagliptin, Linagliptin, Alogliptin

Mechanism Slows breakdown of incretin hormones -> ↑ glucose dep insulin secretion -> ↓ glucagon secretion

Efficacy ↓ A1c 0.5- 0.9%

Advantages Oral, easy dosing, well tolerated Wt neutral No hypos No renal contraindication

Disadvantages S/E: URI sxs, nasopharyngitis, H/A Pancreatitis Saxagliptin- CHF ?potential to interfere with immune fx $$$

Contraindications Hypersensitivity to individual meds

39

DPP- 4 Inhibitors Name Max dose Renal dosing

Januvia® (sitagliptin)

100 mg daily 25-50 mg daily

Onglyza® (saxagliptin)

5 mg daily 2.5 mg daily

Tradjenta® (linagliptin)

5 mg daily Same dose

Alogliptin® (nesina)

25 mg daily 6.25-12.5 mg daily

40

1. DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-29522. Drucker DJ and Nauck MA. Lancet. 2006;368:1696-1705

Properties/EffectGLP-1 Receptor

Agonists1,2DPP-4

Inhibitors1,2

Glu dep insulin production +++ ++

Glu dep decrease in glucagon +++ +

Gastric emptying Delayed No effect

Food intake No effect

Body Weight Neutral

Hypoglycemia No No

Side effects N/V Minimal

Administration SC 1 or 2x/day or weekly

Oral Daily

Incretin Therapies: Major Differences

41

SGLT2 inhibitors

Abdul-Ghani M A et al. Endocrine Reviews 2011;32:515-531

42

SGLT-2 inhibitors

• Canagliflozin (Invokana)- FDA -> 3/13• Dapagliflozin (Farxiga)- FDA -> 1/14• Empagliflozin (Jardiance)- FDA -> 8/14

43

SGLT-2 inhibitors Canagliflozin, Dapagliflozin, Empagliflozin

Mechanism ↑ Urinary excretion of glucose

Efficacy ↓ A1c 0.7-1 %

Advantages Oral, easy dosing Wt loss Possible BP lowering CV benefit (empagliflozin)

Disadvantages UTI; genital infections Hypotension; hyperkalemia Increased calcium excretion DKA

Contraindications eGFR <45 , <60 (Dapagliflozin)

44

SGLT2 Inhibitors and DKA

• 5/15/15 FDA issued warning• 20 cases reported from May 2013 to June

2014 • Euglycemic• ~50% had RF for DKA: eg acute illness,

infection, ↓ insulin dose• Median time to onset after initiation-> 2 wks• Pt education important!

Rosenstock. Euglycemic DKA A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care. 2015 Sep; 38(9): 1638-1642.

45

Human & Analog Insulins in US

Adapted from American Diabetes Association. Diabetes in the Latino Population. Available at: http://www.diabetes.org/uedocuments/LatinoSlidesAugust05.ppt.

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

Plas

ma

Insu

lin L

evel

s

Regular: up to 8 hours

NPH: up to 12 hours

Hours

-U100 glargine: 20–26 hrs -U 300 glargine: up to 36 hrs

-U 100 & U200 degludec: up to 42 hours

aspart, lispro, glulisine: up to 4 hours

-U100 detemir: up to 24 hours

46

Basal/ Bolus Insulin Therapy

Bolus Bolus Bolus

Basal: detemir/ degludec/ glargine

Bolus: aspart/ lispro/ glulisine

B L D Bedtime

Insu

lin E

ffect

B = breakfast L = lunch D = dinner

47

B D L Bedtime

Insu

lin E

ffect

Pre-Mix Insulin: Ex. of Twice Daily Dosing

B = breakfast L = lunch D = dinner

48

Some Newer Insulin Pens TRESIBA U100 & U200 U500 PEN:

COMING SOON

Humulin N (NPH) KwikPen

U300 Toujeo

U200 Humalog

49

Current Concentrations of Insulin in the U.S.

• U-100 = 100 units/ml• U-200 = 200 units/ml• U-300 = 300 units/ml• U-500 = 500 units/ml

50

Pen Needles: Think Comfort

51

Transitions Between Hospital and Home

Diet? Activity level? Oral Agents? Non-insulin injectables?

Insulin?

Carb controlled meal plan,

taken off oral agents & placed on basal/bolus insulin

therapy

Diet? Activity level? Oral Agents? Non-insulin injectables?

Insulin? Follow Up Plan?

Prior to Discharge: Consider A1C, New co-morbidities,

and New contraindications

52

Consider the following at transition:

• If you are admitting someone with pancreatitis, checkthe medication list for incretin therapy, either a DPP-4inhibitor or GLP-1 RA.

• Consider masked, or “euglycemic” DKA in patientson an SGLT-2 inhibitor, particularly in type 1 patients

• At hospital discharge, comorbid conditions are a bigdriver of tailored therapy:

– Renal Insufficiency, with eGFR <30, limits your options significantly:• Safe, high potency options are insulin and thiazolidinediones• Safe, intermediate potency option is a DPP4 Inhibitor

– For heart failure patients, some meds should be avoided: Metformin(biguanide), Thiazodinediones, Saxagliptin (GLP-1 RA)

– For hepatic insufficiency, some meds should be avoided: Sulfonylureas,Glinides, Alpha-glucosidase inhibitors

53

Effective Hospital Discharge:

• Individualized inpatient diabetes self-management education• Mutually agreed upon discharge plan• Clear diabetes-specific instructions that are given to patient

and available to the next provider (PCP)

Rubin, D. Hospital Readmissions of Patients with Diabetes. Current Diabetes Reports, 2015. 15(4): p. 1-9.

54

Transitioning Diabetes Medications at Time of Discharge

55

Pre-Mix Insulins: Beware of “look-alike sound-alikes”

• Humalog mix – 75/25® (75% lispro protamine/25%lispro) & 50/50 (50% lispro protamine/50% lispro)

• Novolog mix – 70/30® (70% aspart protamine/30%aspart)

Human mix: Novolin 70/30® & Humulin 70/30®

Coming Soon? Ryzodeg 70/30 (degludec + aspart)

55

Diabetes Care 2015;38:140 Diabetologia 2015;58:429-442

Basal Only

Basal Plus Pre-Mix

Basal/Bolus

How Many Shots a Day?

56

57

Initiating & Intensifying Insulin: Discharge Regimens to Consider

• Basal Alone: 1 shot/day

• Basal Plus: 2 shots/day

• Pre-Mix: 1-2 shots/day

• Basal-Bolus: 4 shots/day

58

NYP/Cornell Transition Guide To Home

A1c < 7% A1c 7-9% A1c > 9%

Return to same home regimen unless contraindicated

Restart home regimen if not contraindicated, keep basal at 50-100 % of inpatient dose

Best option: Basal insulin at 75-100% of current dose & bolus insulin with meals at fixed or calculated dose Other options: • Basal Plus (basal insulin + bolus

insulin at largest meal)• Pre-mixed insulin before breakfast &

dinner• Basal insulin once daily + repaglinide

with meals• Basal insulin once daily & GLP-1

injectable daily or weeklyBolus insulins: aspart, lispro, glulisine. Pre-Mixed insulins: 70/30, 75/25 & 50/50. Basal insulins: degludec U100 & U200, detemir, glargine U100 & U300.

Adapted with permission from algorithm by Umpierrez, G, Diabetes Care 2014

59

Common Diabetes PrescriptionsCommon Diabetes Prescriptions

Remember to Order Pen Needles with Pens & Syringes with Vials

Instructions BOLUS: NovoLog Flexpen® or Humalog KwikPen® Take (range, up to) units before meals BASAL: Lantus U100 or Toujeo U300 Solostar Pen® or Levemir or Tresiba U100 or U200 FlexTouch Pen® PREMIX: NovoLog Mix 70/30 Flexpen® or Humalog Mix 75/25 KwikPen® NPH: Humulin N Kwik Pen®

Take units at AM/PM OR Take units at AM and Take _____ units at PM

BD Nano or DUO (safety) pen needles DAW* Dispense #100 (or #200) use as directed, DAW* BD Ultrafine 6 mm 3/10 ml insulin syringe (Holds up to 30 units) DAW*

Dispense #100 (or #200) use as directed, DAW*

BD Ultrafine 6 mm 1/2 ml insulin syringe (Holds up to 50 units) DAW*

Dispense #100 (or #200) use as directed, DAW*

BD Ultrafine 6 mm 1 ml insulin syringe (Holds up to 100 units) DAW*

Dispense #100 (or #200) use as directed, DAW*

Accu-Chek Nano, Bayer Contour Next EZ , FreeStyle Freedom LITE OR OneTouch Ultra2 blood glucose meter Dispense: 1 meter

Accu-Chek Nano, Bayer Contour Next EZ , FreeStyle Freedom LITE OR OneTouch Ultra2 test strips Test BG x/day

Accu-Chek Nano, Bayer Contour Next EZ , FreeStyle Freedom LITE OR OneTouch Ultra2 lancets Test BG x/day

60

Inzucci et al. Diabetes Care 2015;38:140-149.

Approach to managementof hyperglycemia：

Patient attitude and expected treatment effortsexpected treat

Disease duration

Life expectancy

Important comorbidities

Established vascular complications

Resources, support system

Risks potentially associated wi th hypoglycemia, otheradverse events

more S t r i n g e n t

lessstringent

highly motivated, adherent,excellent self-care capacities

less motivated, non-adherent,poor self-care capacities

low high

newly diagnosed long-standing

long short

absent few / mild severe

absent few / mild severe

really available limited

61 Inzucchi et al. Diabetes Care. 2015; 38:140-149

62

ABCDs of choosing med

A -> Age, A1c (degree of hyperglycemia)

B -> Body wt/ BMI

C -> Cost/Coverage; Co-morbidities Convenience/Complexity; CV benefit

D -> Defect; Duration of DM

S -> Side effects ; Safety profile

63

• Individualize glycemic targets based on a variety of patientand disease characteristics.

• Diet, exercise, & education are foundations of T2DM therapy.

• Metformin is first choice at diagnosis unless contraindicated.

• After metformin, data are limited. Combination therapy with1-2 other oral / injectable agents is recommended.

• Over time, many patients will require insulin alone or incombination with other agents to maintain glycemic control.

• All treatment decisions should be made in partnership withthe patient, focusing on patient preferences, needs & values.

ADA/EASD Management of Hyperglycemia in T2DM, 2015 Position Statement Summary

64

T2DM Med Charts

• Diabetes Health Type 2 MedicationReference Guide:https://www.diabeteshealth.com/wp-content/uploads/2016/03/Type2.pdf

• MPR Diabetes Treatments Chart:http://www.empr.com/diabetes-treatments/article/123836/

65

References • American Diabetes Association. Standards of Care in Diabetes-2016.

Diabetes Care January 2016 39:S1-119.

• Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1receptor agonist and basal insulin combination treatment for themanagement of type 2 diabetes: a systematic review and meta-analysis. Lancet. 11 September 2014.

• Hinnen DA. Therapeutic Options for the Management of PostprandialGlucose in Patients With Type 2 Diabetes on Basal Insulin. Clinical Diabetes2015;3:175-180.

• Inzucchi SE et al. Management of Hyperglycemia in Type 2 Diabetes, 2015:A Patient Centered Approach: Update to a Position Statement of theAmerican Diabetes Association and the European Association for the Studyof Diabetes. Diabetes Care 2015;38:140–149.

• Davidson MB, Raskin P, Tanenberg RJ, Vlajnic A, Hollander P. A stepwiseapproach to insulin therapy in patients with type 2 diabetes mellitus andbasal insulin treatment failure. Endocrine Practice 2011;17:395–403.