5/16/2018 1 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.
12
Embed
1-Neumiller-Insulin Update - ADA Clinical Conference 2018 ... · • “Insulin stacking” is the excessive accumulation of insulin within the circulation • Typically occurs with
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
5/16/2018
1
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.
5/16/2018
2
ADA 2018: Summary of Glycemic Recommendations
Glycemic Targets: Standards of Medical Care in Diabetes ‐ 2018. Diabetes Care 2018; 41 (Suppl. 1): S55‐S64.
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)
5/16/2018
4
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.
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
5/16/2018
5
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
5/16/2018
6
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
5/16/2018
7
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
• 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
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
5/16/2018
11
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