e4-neumiller & divine ada clinical conference … · for successful insulin use to meet...

5/16/2018

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Insulin Workshop

Joshua J. Neumiller, PharmD, CDE, FASCP

Vice Chair & Associate Professor,

Department of Pharmacotherapy

Washington State University

Spokane, WA

Holly Divine, PharmD, BCACP, BCGP, CDE, FAPhA

Associate Professor

College of Pharmacy

University of Kentucky

Lexington, KY

Disclosures to Participants

Conflicts of Interest and Financial Relationship Disclosures:

Presenters:Joshua J. Neumiller, PharmD, CDE, FASCP

• ADA Editorial Board/Committee Membership:• Editor for the ADA journal Diabetes Spectrum• Member of ADA Professional Practice Committee (PPC)

Holly Divine, PharmD, BCACP, BCGP, CDE, FAPhA• No Disclosures

Learning Objectives

This presentation will cover the following learning objectives:

1. Review current ADA recommendations for the initiation and titration of insulin in people with type 2 diabetes;

2. Discuss key challenges related to the initiation and optimization of insulin therapy in people with type 2 diabetes;

3. Utilize clinical case scenarios to discuss potential strategies for successful insulin use to meet patient‐centered treatment goals.

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Glucose‐Lowering Comparison

Unger J, et al. Postgrad Med. 2010;122(3):145-157.

Cornell S, et al. Postgrad Med. 2012;124(4):84-94.

MonotherapyRoute of

Administration Targets Insulin Resistance

Target Glucose: FPG or PPG

Approximate A1C Reduction

(%)

Sulfonylurea Oral No Both 1.5–2.0

Metformin Oral Yes FPG 1.5

Glitazones Oral Yes Both 1.0–1.5

Meglitinides Oral No PPG 0.5–2.0

AGIs Oral No PPG 0.5–1.0

DDP‐4 inhibitors Oral No PPG 0.5–0.7

SGLT‐2 inhibitors Oral ↓ glucose toxicity Both 0.7–1.1

GLP‐1 agonists Injectable NoShort‐acting – PPGLong‐acting – FPG

0.8–1.5

Amylin analogs Injectable No PPG 0.6

Insulin Injectable ↓ glucose toxicity Basal – FPGBolus – PPG

↓ as much as needed

Insulin PK/PD Comparison

Patient‐specific onset, peak, and duration may vary from times listed in table. Peak and duration are dose‐dependent with shorter durations of action seen for smaller doses and longer durations of action with larger doses.

InsulinTime to Onset of Action (hr)

Time to Peak Action (hr)Duration of Action (hr)

Lispro (U‐100 , U‐200) within 0.25 0.5‐1.5 4‐6

Aspart within 0.25 0.5‐1.5 4‐6

Glulisine within 0.25 0.5‐2 4‐6

Insulin human (inhaled) within 0.25 1 3

Insulin human regular (U‐100) 0.5 3 8

Insulin human regular (U‐500) 0.25 4‐8 13‐24

Human insulin isophane (NPH) 2‐4 4‐10 12‐18

Detemir 3‐4 6‐8 (though relatively flat) Up to 24

Glargine (U‐100) 2‐4 flat 20‐24

Glargine (U‐300) 6 flat up to 36

Degludec (U‐100, U‐200) 1 flat >42

Lispro mix 50/50 within 0.25 0.5‐1.5 Up to 24

Lispro mix 75/25 within 0.25 0.5‐1.5 18‐24

Aspart mix 70/30 within 0.25 1.5‐2.5 Up to 24

Degludec/aspart mix 70/30 within 0.25 1‐2.5 >24

Hirsch IB. N Engl J Med. 2005; 352:174‐83; Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16‐38; Dansinger M. Types of insulin. June 21, 2016. www.webmd.com/diabetes/guide/diabetes‐types‐insulin (accessed 2016 Sep 29); Bennett JA. Insulin chart. July 17, 2015.

www.dlife.com/diabetes/insulin/about_insulin/insulin‐chart (accessed 2016 Sep 29); Individual product prescribing information.

Hirsch IB. N Engl J Med. 2005; 352:174‐83. Flood TM. J Fam Pract. 2007; 56(suppl 1):S1‐S12. Becker RH et al. Diabetes Care. 2015; 38:637‐43.

Pharmacokinetic Profile of Currently Available Single Insulin Products

Plasm

a Insulin

Levels

0 12 16 20 24842 14 18 22106

Intermediate (NPH)

Long (detemir)

Long (U‐100 glargine)

Time (hr)

26 28 30 32 34 36

Ultra‐long

Rapid (aspart, lispro, glulisine, inhaled human insulin)

Short (regular U‐100)

(glargine U‐300)

Mixed short/intermediate (regular U‐500)

Ultra‐long (degludec)

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Antihyperglycemic Therapy in Adults with T2DM

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85





From the Standards:

“If the A1C target is not achieved after approximately 3 months and patient does not have ASCVD, consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP‐4 inhibitor, SGLT2 inhibitor, GLP‐1 receptor agonist, or basal insulin; the choice of which agent to add is based on drug‐specific and patient factors (Table 8.1).”

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See page S77 in:


Hypoglycemic Risk of AntihyperglycemicAgents Added to Metformin

Liu S et al. Diabetes Obes Metab 2012; 14:810‐820

17.8

10.58.9

4.8

1.1 0.9 0.5 0.4 0.6

0

5

10

15

20

25

BiphasicInsulin

TZD SU BasalInsulin

DPP‐4i AGi GLP‐1RA

SGLT‐2iGlinide

Increased Risk vs. Placebo

No Increased Risk vs. Placebo

Odds Ratio vs. Placebo



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Case #1: GD• GD is a 64‐year‐old woman with T2DM of 7 years duration

• Past medical history• Type 2 diabetes mellitus

• Hypertension

• Hyperlipidemia

• Peripheral neuropathy

• Chief complaint“My blood sugar readings aren’t as good as they once were.”

Case #1: GD

• Current medications

• Metformin 1000 mg PO BID

• Sitagliptin 100 mg daily

• Glimepiride 4 mg daily

• Lisinopril 20 mg PO once daily

• Amlodipine 10 mg daily

• Rosuvastatin 20 mg PO once daily

• Duloxetine 60 mg PO once daily

Case #1: GD

• Vital signs• BP: 132/90 mmHg

• Pulse: 70 bpm, regular

• Weight: 198 lb (90 kg)

• Height: 5’6”

• BMI: 32.0

• Labs (fasting)• Glucose: 170 mg/dL

• A1C: 8.1%

• SCr: 1.2 mg/dL

• UACR: 120 mg/g

• eGFR (MDRD): 45 mL/min/1.73m2

• Na: 142 mEq/L

• K: 4.5 mEq/L

• LDL: 90 mg/dL

• HDL: 52 mg/dL

• TG: 130 mg/dL

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Case #1: GD

Social and Family History

• GD is retired and lives with her husband of 40 years

• Weight has been relatively stable for the past year

• GD has never smoked or used illicit drugs

• Drinks 1‐2 glasses of wine with dinner 2‐3 times per week

• Works in the yard on occasion, but is otherwise sedentary

• Mother and father both had T2D

• Private insurance plan with low co‐pays

Case #1: GD’s Blood Glucose Log

Day Morning (Fasting) Bedtime

Monday 185 mg/dL 180 mg/dL

Tuesday 170 mg/dL 192 mg/dL

Wednesday 198 mg/dL 210 mg/dL

Thursday 176 mg/dL 205 mg/dL

Friday 192 mg/dL 121 mg/dL

Saturday 205 mg/dL 230 mg/dL

Sunday 173 mg/dL 202 mg/dL

• GD currently checks her blood glucose twice daily –once in the morning before breakfast and at bedtime

Additional meter download data:• 14‐day average: 186 mg/dL• 30‐day average: 198 mg/dL

Case #1: GD ‐ Questions

1. What would be an appropriate A1C goal for GD?

2. What medication changes would you recommend (if any)?

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ADA 2018: Summary of Glycemic Recommendations

Glycemic Targets: Standards of Medical Care in Diabetes ‐ 2018. Diabetes Care 2018; 41 (Suppl. 1): S55‐S64.

Determining an Appropriate A1C Target

low high

newly diagnosed long-standing

long short

absent severeFew/mild

absent severeFew/mild

highly motivated, adherent, excellent self-care capabilities

readily available limited

less motivated, nonadherent, poor self-care capabilities

A1C7%

more stringent

less stringentPatient/Disease Features

Risk of hypoglycemia/drug adverse effects

Disease Duration

Life expectancy

Important comorbidities

Established vascular complications

Patient attitude & expected treatment efforts

Resources & support system

Glycemic Targets: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S55-S64

Case #1: GD – Basal Insulin Initiation

• GD’s primary care provider (PCP) would like to start her on U‐100 insulin glargine.

3. What would you recommend as a starting dose?

4. What titration schedule/approach would you recommend?

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American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74

Basal Insulin Initiation in T2DM:• Start with 10 units/day or 0.1‐

0.2 units/kg/day• Adjust 10‐15% or 2‐4 units

once or twice weekly to reach FBG target

• Assess and adjust for hypoglycemia


Treat‐to‐Target Strategy for Basal Insulin Titration

Riddle JC. Diabetes Care. 2003;26:3080‐3086.

Mean of FPG from preceding 2 days

Increase insulin dose (units/day)

≥180 mg/dL 8 units

140‐180 mg/dL 6 units

120‐140 mg/dL 4 units

100–120 mg/dL 2 units

<100 0 units

*No increase in dosage if BG <72 mg/dL in preceding week; dose decreases of 2‐4 units/day allowed if BG <56 mg/dL in preceding week.

Start with 10 units/day bedtime basal and adjust weekly

Insulin Glargine Titration: Physician vs. Patient‐Directed Titration

Davies M, et al. Diabetes Care. 2005;28:1282‐1288.

Mean of FBBG from previous 3 consecutive

days

Increase in insulin glargine dose (units/day)

Algorithm 1: Physician‐Directed

(at each visit)

Algorithm 2: Patient‐Driven(every 3 days)

≥180 mg/dL 6‐8 units 2 units

140‐180 mg/dL 4 units 2 units

120‐140 mg/dL 2 units 2 units

100–120 mg/dL 0‐2 units 0‐2 units

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Insulin Glargine Titration: Physician vs. Patient‐Directed Titration

Davies M, et al. Diabetes Care. 2005;28:1282‐1288.

3‐0‐3 Strategy for Basal Insulin Self‐Titration

Meneghini L. Diabetes Obes Metab. 2007;9:902‐913.

Mean of FPG from preceding 3 days

Change in insulin dose (units/day)

<80 mg/dL ↓ by 3 units

80‐110 mg/dL No Change

>110 mg/dL ↑ by 3 units

*Self‐adjust basal insulin every 3 days

Case #1: GD – Basal Insulin Initiation

5. What counseling/support would you recommend for GD at this time?

6. When starting basal insulin in this scenario, would you discontinue any of her current antihyperglycemic agents?

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Barriers to Effective Insulin Use

Minze MG, et al. J Fam Pract 2011;60(10):577‐580

Common Barriers for People with Diabetes• Psychological

• Insulin represents failure• Lack of perceived benefit• Pain/fear of injections• Belief that insulin is complicated• Loss of independence/change in lifestyle

• Stigma related to needle use

• Harmful effects• Hypoglycemia• Weight gain

• Financial

Common Barriers for Providers

• Negative feelings about insulin

• Time constraints

• Lack of support/resources• Concern about adverse effects

• Hypoglycemia• Weight gain

• Fear of patient response/lack of adherence

Therapeutic Inertia: Barriers and Solutions to Insulin Therapy

Russell‐Jones D, et al. Diabetes Obes Metab 2018;20:488‐496

Solutions

Barriers

Improved Therapies

Nurse Management; Specialist Feedback

Support from a

Psychologist

Improved Devices

DSME; Mobile Apps

Fear of Injection

TherapeuticInertia

Burdensome Regimens

Side Effects

Poor Communication

Negative Appraisals of Insulin

Overcoming Barriers to Insulin Therapy: Potential Strategies

• Motivational interviewing

• Avoid using insulin as a “threat” • Use insulin as a solution

• Discuss it as an option early

• Use insulin pens and regimens that offer maximum flexibility

• Give a “limited” trial of insulin

• Give an injection in the office/clinic

• Teach patient to recognize and treat hypoglycemia

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Hypoglycemia Treatment: Rule of 15

1. If blood glucose <70 mg/dL, consume 15 grams of quick‐acting carbohydrate;

2. Wait 15 minutes;

3. Re‐check blood glucose;

4. If still <70 mg/dL – consume another 15 grams of carbohydrate;

5. If >70 mg/dL, consume a snack or meal within 60 minutes

Continuation of Non‐Insulin Agents with Insulin?

• Continued use of metformin, SGLT‐2 inhibitors and GLP‐1 receptor agonists may mitigate weight gain

• Thiazolidinediones plus insulin can result in significant weight gain/edema

• Must consider medication burden and cost• May consider elimination of sulfonylureas, DPP‐4 inhibitors, TZDs and meglitinides

Riddle MC. Diabetes Care 2008;31(Suppl 2):S125‐S130.Vos RC, et al. Cochrane Database of Systematic Reviews 2016;9:CD006992.

Case #1: GD

Case Debrief

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Case #2: RL

• RL is a 66‐year‐old man with T2DM of 14 years duration

• Past Medical History• Type 2 diabetes mellitus• Hypertension• Hyperlipidemia• Hypothyroidism• History of MI 6 years ago

• Chief complaint“My blood sugars are high at night before I go to bed.”

Case #2: RL

Current Medications• Metformin 1000 mg PO BID

• Insulin detemir 42 units once daily QHS

• Fosinopril 20 mg PO once daily

• Hydrochlorothiazide 25 mg PO once daily

• Atorvastatin 40 mg PO once daily

• Levothyroxine 100 mcg PO once daily

• Aspirin 81 mg once daily

• Ibuprofen 400 mg QID PRN

Case #2: RL

Social and Family History

• RL lives with his wife of 28 years

• RL works part time (20 hours per week) as a grocery store clerk

• He is adherent to his current medication regimen

• RL engages in minimal physical activity• Golf on Saturdays

• Father died from an MI at the age of 65

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Case #2: RL

• Vital signs• BP: 152/92 mmHg

• Pulse: 72 bpm, regular

• Weight: 225 lbs (102 kg)

• Height: 6’0”

• BMI: 30.5

• Labs (fasting)• Glucose: 125 mg/dL

• A1C: 8.4%

• SCr: 1.1 mg/dL

• UACR: 40 mg/g

• eGFR (CKD‐EPI): 70 mL/min/1.73m2

• Na: 136 mEq/L

• K: 4.6 mEq/L

• LDL: 82 mg/dL

• HDL: 42 mg/dL

• TG: 156 mg/dL

Case #2: RL’s Blood Glucose Log

Day Morning (Fasting) Bedtime*

Monday 132 mg/dL

Tuesday 112 mg/dL 195 mg/dL

Wednesday 141 mg/dL

Thursday 115 mg/dL

Friday 132 mg/dL 230 mg/dL

Saturday 152 mg/dL 202 mg/dL

Sunday 123 mg/dL

• RL checks his blood glucose once to twice daily

*RL explains that he only checks his blood glucose at bedtime if he “doesn’t feel right.”

Case #2: RL ‐ Questions

1. What additional questions would you have for RL?

2. What medication changes would you recommend (if any) at this time?

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Case #2: RL’s Follow‐Up Blood Glucose Log

Day Breakfast Lunch Pre‐Dinner Bedtime

Before After Before After

Monday 115 mg/dL 140 mg/dL 132 mg/dL 183 mg/dL 221 mg/dL

Tuesday 141 mg/dL 170 mg/dL 154 mg/dL 192 mg/dL 170 mg/dL 189 mg/dL

Wednesday 108 mg/dL 153 mg/dL 172 mg/dL 202 mg/dL 263 mg/dL

• RL was asked to check his blood glucose more frequently and provide some additional data as shown below:

Case #2: RL – Basal Insulin Switch

• RL’s PCP believes his insulin detemir may be “wearing off” late in the day and would like to switch him to a longer‐acting basal insulin analog.

3. Which insulin product would you recommend?

4. How would you recommend converting RL to the new insulin product?

Reasons for Insulin Product Switching

• Medical Switching• Regimen complexity considerations

• Adherence

• Hypoglycemia

• Glycemic control

• Weight considerations

• Dosing limitations (large insulin doses/injection)

• Non‐Medical Switching• Formulary restrictions/changes

• Cost

• Care transitions

Nguyen E, et al. Curr Med Res Opin 2016;32:1281‐1290.Parkin C, Meece J. AADE in Practice 2017;16‐21.

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Case #2: RL

• RL was switched to U‐100 insulin degludecand has been titrated to achieve his fasting blood glucose target. His PCP would now like to add an agent to target postprandial glucose because his A1C is still elevated at 7.9%.

5. What would you recommend to add at this time?

Postprandial vs. Fasting Hyperglycemia on A1C

Monnier L, et al. Diabetes Care. 2003;26:881-5.

Fasting

PPG


Once FBG optimized – target PPG excursions:• Add 1 rapid‐acting insulin injection to largest meal, or

• Add GLP‐1 RA, or• Change to premixed insulin twice daily


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A1C Change From Baseline to Week 24

Davidson MB et al. Endocr Pract 2011;17(3):395-403.

Following 14-week run-in with insulin glargineMean A1C decreased from >10.0% to ~8.0%288 patients achieved A1C 7.0%Final dose was 0.55 U/kg regardless of reaching target





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• In patients with T2DM and established ASCVD, antihyperglycemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse CV events and CV mortality (currently empagliflozin and liraglutide), after considering drug‐specific and patient factors (Table 8.1). A

• In patients with T2DM and established ASCVD, after lifestyle management and metformin, the antihyperglycemic agent canagliflozin may be considered to reduce major adverse CV events, based on drug‐specific and patient factors (Table 8.1). C


Pharmacologic Therapy For T2DM: Recommendations

Start with basal insulin

Titration

If A1c 7‐7.5%,* despite titration

Intensify insulinAdd GLP‐1receptor agonist

*or an individualized target

CONSIDERATIONS

•Weight gain• Hypoglycemia risk• Large doses of insulin often needed

•Weight loss• Reduced risk of hypoglycemia

• Similar efficacy to prandial insulin

Additional prandial injections

CONSIDERATIONS

Basal “Plus”

Multiple Daily Inj.

• GI adverse effects• Pancreatitis‐ avoid • Treat to target

• Good efficacy

GLP‐1 Receptor Agonist vs. Bolus Insulin in T2DM Patients with Optimized Basal Insulin

Diamant M et al. Diabetes Care. 2014; 37:2763‐73.

∆A

1c,

%

0-1.5

-1.0

-0.5

0.0

302 18 24

Lispro

Exenatide BID

Weeks Since Randomization4 6 8 12

∆F

PG

, m

mo

l/L

0-1.0

-0.5

0.5

1.0

302 18 24Weeks Since Randomization

4 6 8 12

0.0

Blo

od

G

luco

se,

mm

ol/

L

PreBreakfast

∆B

od

y W

eig

ht,

kg

0-3

0

23

302 18 24Weeks Since Randomization

4 6 8 12

1

-1-2

Post Pre Post Pre Post 3AMLunch Dinner

bb

bbbbbb

a a a aa

a a a

5

7

9

11

ap<0.01 for exenatide BID vs. insulin lisprobp<0.001 for exenatide BID vs. insulin lispro

Compared with lispro, exenatide caused more GI issues (47% vs. 13%), but fewer non‐nocturnal hypoglycemic episodes (15% vs. 34%)

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Insulin Glargine/Lixisenatide Fixed‐Dose Combination

• Fixed‐dose combination product• Insulin glargine U‐100

• Lixisenatide (short‐acting GLP‐1RA) – 33 mcg/mL

• Initiation:• For patients on < 30 units basal insulin:

• 15 units insulin glargine U‐100 (5 mcg lixisenatide)

• For patients on 30 ‐ 60 units basal insulin:

• 30 units insulin glargine U‐100 (10 mcg lixisenatide)

• Administration: within 1 hour before the first meal of the day

• Titration: 2 ‐ 4 units (insulin glargine U‐100 component) once weekly on the basis of FPG

• Max dose: 60 units insulin glargine U‐100/20 mcg lixisenatide• Pen device delivers 15‐60 units of insulin glargine

Insulin glargine/lixisenatide Prescribing Information. Available at: http://products.sanofi.us/Soliqua100‐33/Soliqua100‐33.pdf

Insulin Degludec/Liraglutide Fixed‐Dose Combination

• Fixed‐dose combination product • Insulin degludec U100 • Liraglutide (once‐daily GLP‐1RA) – 3.6 mg/mL

• Initiation:• 16 units insulin degludec (0.58 mg liraglutide) once daily

• Administration: same time once daily (with or without food)

• Titration: • Titrate by 2 units (insulin degludec) every 3 ‐ 4 days on the basis of FPG (or hypoglycemia)

• Max dose: 50 units insulin degludec/1.8 mg liraglutide• Pen device delivers 10‐50 units of insulin degludec

Insulin degludec/liraglutide Prescribing Information. Available at: http://www.novo‐pi.com/xultophy10036.pdf





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Premixed Insulin Administration

B SL HS

Insu

lin E

ffec

t

B

Aspart 70/30


If additional intensification is needed:• Basal‐bolus (≥2 rapid‐acting injections with meals)

• Premixed analog 3 times daily


Case #2: RL

Case Debrief

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Standards of Care – Potentially Useful Resources

• Full version available• Abridged version for PCPs• SOC slide deck• Free app • Pocket cards with key figures• Free webcast for continuing education credit

Professional.Diabetes.org/SOC

Thank you

e4-neumiller & divine ada clinical conference … · for successful insulin use to meet...

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