1-Neumiller-Insulin Update - ADA Clinical Conference 2018 ... · • “Insulin stacking” is the...
Transcript of 1-Neumiller-Insulin Update - ADA Clinical Conference 2018 ... · • “Insulin stacking” is the...
5/16/2018
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Insulin Update: New and Emerging Insulins
Joshua J. Neumiller, PharmD, CDE, FASCP
Vice Chair & Associate Professor,
Department of Pharmacotherapy
Washington State University
Spokane, WA
Disclosures to Participants
Conflicts of Interest and Financial Relationship Disclosures:
Presenter:
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)
Learning Objectives
This presentation will cover the following learning objectives:
1. Review the pharmacokinetic and clinical characteristics of currently available insulin products;
2. Discuss considerations for use of newer, ultra‐long acting basal insulin products; and
3. Discuss the potential role of fixed‐dose insulin/GLP‐1 receptor agonist products in the management of type 2 diabetes.
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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
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
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See page S77 in:
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
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
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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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
Regular U‐100/NPH 70/30 within 0.5 3 12‐18
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.
*Follow‐on products available
†Insulin aspart is available in 2
formulations; Fiasphas a relatively fast onset of action
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
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
U‐300 Insulin Glargine: Determining Starting Dose (and Dose
Conversion) in T2DM
Prior Treatment: Start with:
Once‐daily basal insulin 1:1 conversion*
Twice‐daily NPH 80% of total daily NPH dose
No current basal insulin 0.2 units/kg
U‐300 Insulin Glargine Prescribing Information. Available at: http://products.sanofi.us/toujeo/toujeo.pdf
• Only available in pens• Just dial the prescribed dose ‐ no “conversion” needed
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Insulin Glargine U100 vs U300 in T2DMMeta‐Analysis of 3 Phase 3 Studies
Cumulative
Mean Events
dCumulative
Mean Events
d
Weeks of Treatment
Any Time of Day, 24 h
00
4
810
282 18 244 6 8 12
6
2
262220161410
00
0.5
1.5
2.0
282 18 244 6 8 12
1.0
262220161410
Nocturnal, 00:00‐05:59 h
A1c, %
Glargine U100
Glargine U300
7.0
7.8
8.2
8.4
8.0
7.6
7.4
7.2
Baseline Week 12 Month 6
aP<0.001; bP<0.05; cP=NS; dConfirmed hypoglycemia (≤70 mg/dL) or severe hypoglycemia.N=1247 patients treated with glargine U300 and 1249 treated with glargine U100 in 3 phase 3 EDITION studies.
Glargine U100
Glargine U300
‐1.02%
‐1.02%LSM Difference, 0.00%c
(95% CI, ‐0.08–0.07) Annual Rate Ratio U300/U100, 2.10/3.06=0.69a(95% CI, 0.57–0.84)
Annual Rate Ratio U300/U100, 15.22/17.73=0.86b
(95% CI, 0.77–0.97)
Glargine U100
Glargine U300
•Weight gain –Glargine U100, +0.79 kg–Glargine U300, +0.51 kg–LSM Difference, ‐0.28 kgb
•Weight gain –Glargine U100, +0.79 kg–Glargine U300, +0.51 kg–LSM Difference, ‐0.28 kgb
Ritzel R, et al. Diabetes Obes Metab. 2015;17(9):859‐867.
Flexible vs Fixed Dosing U‐300 Glargine: Sub‐Studies of Phase III Trials
Riddle MC, Bolli GB, Home PD, et al. Diabetes Technol Ther 2016;18(4):252-257.
• 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
Per
ce
nta
ge
of
Inje
ctio
ns
(%)
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 dosing
Fixed dosing
6 months (randomization, sub-study)
U-300 once dailyevery 24 ± 3 h
U-300 once dailyevery 24 h
9 months (end of sub-study)
sub-study
6-Month Treatment Period(main study)
6-Month Extension Period(main study)
U-300 once dailyevery 24 h
Insulin Degludec: Determining a Starting Dose in T2DM
Prior Treatment: Start with:
Long or Intermediate‐acting insulin
Same unit dose as the current total daily dose
No current basal insulin 10 units once daily
• Only available in pens• 100 units/mL or 200 units/mL• Just dial the prescribed dose; no “conversion” needed
Insulin degludec prescribing information. Available at: http://www.novo‐pi.com/tresiba.pdf
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BEGIN Type 2 ‐ Hypoglycemia
(A)Overall confirmed hypoglycemic episodes. (B) Nocturnal confirmed hypoglycemic episodes. (C) Diurnal Confirmed hypoglycemic episodes. (D) Cumulative # of hypoglycemic episodes per participant during 24 h
Lower rates of hypoglycemia: overall and nocturnal
Garber A et al. Lancet. 2012;379(9825):1498–1507.
Flexible vs Fixed Dosing of Insulin Degludec
Meneghini L, et al. Diabetes Care 2013;36:858‐864.
Ultra‐Long Acting Insulin Comparison
Product Availability Dosing Range
(per injection)
U‐300 insulin
glargine
SoloStar® prefilled pens
(450 units/pen)
1‐80 units
(1 unit increments)
Max SoloStar® prefilled pens
(900 units/pen)
2‐160 units
(2 unit increments)
Insulin degludec U‐100 FlexTouch® pen
(300 units/pen)
1‐80 units
(1 unit increments)
U‐200 FlexTouch® pen
(600 units/pen)
2‐160 units
(2 unit increments)
U‐300 Insulin Glargine Prescribing Information. Available at: http://products.sanofi.us/toujeo/toujeo.pdfInsulin degludec prescribing information. Available at: http://www.novo‐pi.com/tresiba.pdf
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Insulin Stacking vs. Therapeutic Accumulation
• “Insulin stacking” is the excessive accumulation of insulin within the circulation
• Typically occurs with the administration of rapid‐acting insulin to correct hyperglycemia
• Described as:• “…the practice of providing correctional doses of insulin before a prior dose of prandial insulin (or the peak action of neutral protamine Hagedorn, [NPH]) has had its full effect.”1
• “…previously infused insulin still has an effect on future glucose values.”2
1Hirsch IB. N Engl J Med. 2005; 352:174‐83.2Bequette BW. J Diabetes Sci Technol. 2009; 3:1005‐13.
Potential for Insulin Stacking with Rapid‐acting Insulin
Heise T, Meneghini LF. Endocr Pract. 2014; 20:75‐83.
Insulin Stacking vs. Therapeutic Accumulation
• Therapeutic, or steady‐state accumulation is a normal part of the PK process
• Enables long‐acting insulin to reach a stable, steady‐state condition
• Important to dose the basal insulin in appropriate amounts and titrate at appropriate time intervals to allow for steady‐state accumulation and avoid “overshooting” the target fasting blood glucose
Heise T, Meneghini LF. Endocr Pract. 2014; 20:75‐83.
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Therapeutic Accumulation with Once Daily Administration of Long‐acting Insulin:
Impact of a Missed Dose
Heise T, Meneghini LF. Endocr Pract. 2014; 20:75‐83.
Serum Concentration
(% M
axim
um)
12.5‐hr half‐life 25‐hr half‐life
Treatment Days Treatment Days
121110 19181716151413 20 121110 19181716151413 200
180
160
140
120
100
80
60
40
20
200
U‐200 Insulin Lispro
• Available in 3mL prefilled pen
• 600 units per vial (versus 300 units/vial for U‐100 lispropens)
• Can administer 1‐60 units/injection
Insulin lispro Prescribing Information. Available at: http://uspl.lilly.com/humalog/humalog.html#pi
Pharmacokinetic Profiles of Currently Available Insulin Products
Plasm
a insulin
levels
0 12 16 20 24842 14 18 22106
Intermediate‐acting (NPH insulin)
Long‐acting (insulin detemir)
Long‐acting (insulin glargine)
Time (h)
26 28 30 32 34 36
Ultralong‐acting
(insulin glargine U300)
Rapid‐acting (insulins aspart, lispro, glulisine; insulin human [inhaled])
Regular insulin U‐100
Ultralong‐acting (insulin degludec U100, U200)
Regular U‐500
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.
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U‐500 Regular Insulin
• Concentrated human insulin• 20‐mL vials
• U‐500 insulin syringes now available
• 3‐mL pen (1,500 units/pen) now available
• Reduced hexamer formation leads to faster dissociation and absorption
• Time to peak: 30 minutes
• Half‐life: ~4 hours
• Indication• Patients requiring > 200 units of insulin/day
Lamos EM, et al. Ther Clin Risk Manag. 2016; 12:389‐400.
Hood RC, et al. Endocr Pract. 2015; 21:782‐93.
Steps for Initiating U‐500 Insulin
• Total daily dose determination
• Dose proportion determination
1 month prior: A1c >8%&
Within 1 week prior: BG ≥183 mg/dL
1 month prior: A1c ≤8%OR
Within 1 week prior: BG <183 mg/dL
TDD: 100% of U‐100 dose TDD: 80% of U‐100 dose
Before Breakfast Before Lunch Before Dinner
BID regimen 60% 0% 40%
TID regimen 40% 30% 30%
Hood RC et al. Endocr Pract. 2015; 21:782‐93.
U‐500 Insulin Titration: BID Regimen
Insulin Dose to Adjust
Blood Glucose Value Reviewed Blood Glucose Value (mg/dL)
Action
Prebreakfast Median predinner ORmedian prelunch
≤70 ↓10%
Median predinner 71‐130 No change
131‐180 ↑5%
181‐220 ↑10%
>220 ↑15%
Predinner Median prebreakfast, median bedtime, OR 3 AM value
≤70 ↓10%
Median prebreakfast 71‐130 No change
131‐180 ↑5%
181‐220 ↑10%
>220 ↑15%
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Hood RC et al. Endocr Pract. 2015; 21:782‐93.
U‐500 Insulin Titration: TID RegimenInsulin Dose to Adjust Blood Glucose Value Reviewed Blood Glucose Value
(mg/dL)Action
Prebreakfast Median prelunch ≤70 ↓10%
71‐130 No change
131‐180 ↑5%
181‐220 ↑10%
>220 ↑15%
Prelunch Median predinner ≤70 ↓10%
71‐130 No change
131‐180 ↑5%
181‐220 ↑10%
>220 ↑15%
Predinner Median prebreakfast, median bedtime, OR 3 AM value
≤70 ↓10%
Median prebreakfast 71‐130 No change
131‐180 ↑5%
181‐220 ↑10%
>220 ↑15%
Who may Benefit from Concentrated Insulins?
• Patients not receiving a full 24 hours of fasting coverage with their current basal insulin product
• Patients with hectic/erratic schedules
• Patients who require large daily doses of insulin
• Patients experiencing nocturnal hypoglycemia with their current basal insulin (?)
American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74
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
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
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GLP‐1RA vs. Bolus Insulin in Patients with T2DM and Optimized Basal Insulin
Diamant M, et al. Diabetes Care. 2014;37(10):2763‐2773.
ΔA1C (%)
0‐1.5
‐1.0
‐0.5
0.0
302 18 24
Insulin lispro
Exenatide BID
Weeks since randomization
4 6 8 12
ΔFPG (mmol/L)
0‐1.0‐0.5
0.51.0
302 18 24
Weeks since randomization
4 6 8 12
0.0
Blood glucose (mmol/L)
PreBreakfast
ΔBody weight (kg)
0‐3
0
23
302 18 24
Weeks 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
Exenatide caused more gastrointestinal issues (47% vs. 13%) but fewer non‐nocturnal episodes of hypoglycemia (15% vs. 34%) compared with insulin lispro
Hypoglycemia Risk Relative Risk (95% CI) Weight, %Diamant et al (2014) 0.70 (0.55 to 0.90) 50.42Rosenstock et al (2014) 0.65 (0.50 to 0.83) 49.21Shao et al (2014) 0.14 (0.01 to 2.65) 0.37Overall (I2=0.0%, P=0.526) 0.67 (0.56 to 0.80) 100.00
∆A1c Weighted Mean Difference (95% CI) Weight, %
Diamant et al (2014) ‐0.03 (‐0.17 to 0.11) 32.25Rosenstock et al (2014) ‐0.16 (‐0.33 to 0.01) 22.50Shao et al (2014) ‐0.11 (‐0.23 to 0.01) 45.25Overall (I2=0.0%, P=0.470) ‐0.10 (‐0.17 to ‐0.02) 100.00
GLP‐1 RAs + Basal Insulin vs Basal‐Bolus Insulin: A Meta‐analysis
Eng C, et al. Lancet. 2014;384(9961):2228‐2234.
∆Body Weight Weighted Mean Difference (95% CI) Weight, %
Diamant et al (2014) ‐4.60 (‐5.33 to ‐3.87) 33.66Rosenstock et al (2014) ‐1.50 (‐2.06 to ‐0.94) 33.81Shao et al (2014) ‐11.07 (‐12.59 to ‐9.55) 32.53Overall (I2=98.7%, P<0.0001) ‐5.66 (‐9.80 to ‐1.51) 100.00
Favors GLP-1 RA + Basal Insulin Favors Basal-Bolus Insulin
-0.3 -0.2 -0.1 0 0.1 0.2 0.3
0.008 1 4.9
-10 -6 -2 0 2 6 10
Fixed‐Combination Basal + GLP‐1 Injectables
• Insulin glargine/lixisenatide
• Insulin degludec/liraglutide
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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
Thank you!