Newer Insulins Boca Raton Regional Hospital 15th Annual Internal Medicine Conference Luigi F. Meneghini, MD, MBA Professor of Internal Medicine, UT Southwestern Medical Center Executive Director, Global Diabetes Program, Parkland Health & Hospital System luigi.meneghini@utsouthwestern.edu
Agenda Brief history of insulin development ADA guidelines for insulin management Longer-acting basal insulin analogs Faster-acting insulin aspart Fixed-ratio combinations with insulin + GLP-1 agonists Resurgence of Regular U500
FDA approved medications to treat diabetes 74 Gourgari et al. Journal of Diabetes and Its Complications 31 (2017) 1719 1727
Historical approval of insulin preparations by the FDA Humulin R U500 Humulin R U100 Humulin NPH Humulin 70/30 Novolin 70/30 Novolin R U100 Novolin NPH Humalog U100 Humalog 50/50 Humalog 75/25 Lantus 1982 1989 1991 1996 1999 2000 2001 2004 2005 2014 2015 2016 2017 Novolog 70/30 Apidra Levemir Afrezza Toujeo U300 Humalog U200 Tresiba Ryzodeg 70/30 Basaglar Soliqua Xultophy FIASP Admelog
Insulin products marketed in the US Prandial Basal Combinations Short-acting Regular U100 (Humulin R, Novolin R, ReliOn R) Regular U500 (Humulin U500) Rapid-acting Glulisine (Apidra) Aspart (Novolog) Lispro (Humalog U100 & U200, Admelog) Faster-acting aspart (FIASP) Inhaled Technosphere insulin (Afrezza) Post-prandial control Intermediate, basal NPH (Humulin N, Novolin N, Relion N) Basal analogs Glargine U100 (Lantus, Basaglar) Detemir (Levemir) Longer-acting basal analogs Degludec (Tresiba U100 & U200) Glargine U300 (Toujeo) Fasting control Adapted from Meneghini LF. New insulin preparations: a primer for the clinician. Cleveland Clinic Journal of Medicine 2016; 83(1): S43-S49 Pre-mixed Insulin 70/30 (Regular, Novolog Mix) Insulin 75/25 (Humalog Mix) Degludec/aspart 70/30 (Ryzodeg) Aspart 50/50 (Humalog Mix) Fixed-ration combinations Glargine U100/Lixisenatide (Soliqua) Degludec U100/Liraglutide (Xultophy) Fasting & post-prandial control
Insulin products marketed in the US Prandial Basal Combinations Short-acting Regular U100 (Humulin R, Novolin R, ReliOn R) Regular U500 (Humulin U500) Rapid-acting Glulisine (Apidra) Aspart (Novolog) Lispro (Humalog U100 & U200, Admelog) Faster-acting aspart (FIASP) Inhaled Technosphere insulin (Afrezza) Post-prandial control Intermediate, basal NPH (Humulin N, Novolin N, Relion N) Basal analogs Glargine U100 (Lantus, Basaglar) Detemir (Levemir) Longer-acting basal analogs Degludec (Tresiba U100 & U200) Glargine U300 (Toujeo) Fasting control Adapted from Meneghini LF. New insulin preparations: a primer for the clinician. Cleveland Clinic Journal of Medicine 2016; 83(1): S43-S49 Pre-mixed Insulin 70/30 (Regular, Novolog Mix) Insulin 75/25 (Humalog Mix) Degludec/aspart 70/30 (Ryzodeg) Aspart 50/50 (Humalog Mix) Fixed-ration combinations Glargine U100/Lixisenatide (Soliqua) Degludec U100/Liraglutide (Xultophy) Fasting & post-prandial control
ADA Guidelines on injectable therapy Diabetes Care 2018; 41 (Suppl. 1): S73-S85
Basal insulin replacement
Basal Insulin Analogs towards flatter, longer, and more consistent biologic profiles Mathieu, et al. Nature Reviews 2017; 13: 385-399
Biologic activity & mode of protraction Mathieu, et al. Nature Reviews 2017; 13: 385-399
Basal Insulin Efficacy in lowering A1C NPH = Glargine U100 = Detemir* = Degludec = Glargine U300* = Glargine U100 biosimilars * May require 10%-15% more units.
GIR, mg/kg/min Action of Long vs Ultralong-Acting Insulins 3 2 U-100 glargine (0.4 U/kg) 1,a 1 0 3 2 1 0 3 2 1 0 U-300 glargine (0.4 U/kg) 1,2,b U-100 degludec (0.4 U/kg) 2,b,c 0 6 12 18 24 30 36 42 Time After Injection, hours 1. Becker RH, et al. Diabetes Care. 2015;38:637-643; 2. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda; 3. Heise T, et al. Diabetes. 2012;61(suppl 1):A91 [abstract 349-OR].
Longer-acting basal analogs have lower hypoglycemia risk (esp. nocturnal) than glargine U100 Hypoglycemia Risk Glargine U300 Degludec < Glargine U100 < NPH Becker RH, et al. Diabetes Care. 2015;38:637-643. US FDA. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/drugsatfda. Heise T, et al. Diabetes. 2012;61(Suppl 1):A91 [abstract 349-OR]. Bolli GB, et al. Diabetes Obes Metab. 2015;17:386-394
3-Point MACE 0.91 HbA 1c Reduction = Severe Hypoglycemia Overall Nocturnal -40% -53% Values in red are statistically significant. MACE, major adverse cardiovascular event. Marso SP, et al. NEJM 2017; 377: 723-732
Basal Insulin Replacement Options: Hypo Risk vs Cost Cost ($) Degludec $312 Glargine U300 $203 Detemir $284 Glargine U100 $178 NPH $28 Hypoglycemia risk Cost of 1000 units of insulin from GoodR x based on Walmart pricing (pens or vials, when available). www.goodrx.com. Accessed October 3, 2017.
When Might Ultra Long-Acting Insulin Be Considered? Patients experiencing nocturnal hypoglycemia with current basal insulins (glargine U100) Patient on small basal insulins doses not lasting throughout the day (i.e. <20 u/day) Specific insulin requiring populations Cystic fibrosis Hypoglycemia unawareness Very thin
What time of the day do you start the basal insulin? > = NPH Detemir Glargine U100 Glargine U300 Degludec
Average glucose profiles, mean (SE), mg/dl 24-hour glucose profile of AM vs PM administration of Gla-100 or Gla-300 in T1DM 201 Gla-100 201 Gla-300 183 183 165 165 146 128 Morning Evening 0 2 4 6 8 10 12 14 16 18 20 22 24 Time, h 146 128 Morning Evening 0 2 4 6 8 10 12 14 16 18 20 22 24 Time, h Average 24-h glucose profiles during the last 2 weeks of each treatment period Bergenstal RM, et al. Diabetes Care 2017;40:554 60
Basal insulin Up-titration: Practical Tips Glycemic targets FPG < 130 mg/dl & A1C < 7% FPG < 150 mg/dl & A1C < 8% MD or patient driven Titration algorithms or 1unit:1day 3units:3days 2,4,6,8units:7days or
Basal insulin titration above 0.5 units/kg/day associated with more weight gain and hypoglycemia risk & less impact on A1C Reid T, et al. Int J Clin Pract. 2016;70(1):56-65. N=2837 insulin-naïve T2D Patients requiring 0.5 u/kg/d had higher baseline A1C, were younger, & had shorter diabetes duration
Total Hyperglycemia (%) Glycemic contributions after optimizing basal insulin therapy Basal hyperglycemia Postprandial hyperglycemia 100 80 60 40 20 0 <6.5% 6.5-<7.0% 7.0-<7.5% 7.5-<8.0% 8.0% Baseline HbA1c Category (%) Riddle MC, et al. Diabetes Care. 2011:34:2508-2514.
Going beyond basal insulin therapy Post-prandial glycemic control
Adding Prandial Insulin to Basal Therapy Further Improves HbA 1C Davies M et al Diabetes Obes Metab. 2008 May;10(5):387-99.
Adding sequential prandial boluses to basal insulin therapy Identify the largest meal of the day Start 4-6 units of prandial insulin Adjust dose based on SMBG Most patients need around 10-12 units before meals If A1C still above target after optimization of 1 st bolus, add 2 nd prandial bolus Hypoglycemia risk increases with each additional bolus Meneghini LF, et al. Endocr Pract. 2011; 17: 727-736
Biologic activity & mode of protraction Mathieu, et al. Nature Reviews 2017; 13: 385-399
Faster-Acting Insulin Aspart (FIASP) versus Regular insulin and other prandial analogs Price/vial $24 $289 $174-290 Faster-acting insulin aspart Consider when: Need better postprandial control Post-meal dosing Insulin pumps Pregnancy? Mathieu, et al. Nature Reviews 2017; 13: 385-399
Faster-Acting Insulin Aspart (FIASP) versus Regular insulin and other prandial analogs Price/5 pens n/a $550 $420-550 Faster-acting insulin aspart Consider when: Need better postprandial control Post-meal dosing Insulin pumps Pregnancy? Mathieu, et al. Nature Reviews 2017; 13: 385-399
Adding GLP-1 agonists to basal insulin
Basal Insulin Intensification: GLP-1 RA vs Prandial Insulin Meta-Analysis A1C 7.0% a Equivalent glycemic control (P = NS) 2,3 I 2 = 12.0% 0.636 1 1.57 Favors basal-bolus insulin Favors GLP-1 + basal insulin Relative Risk (95% CI) 1.01 (0.85, 1.21) 1.20 (0.92, 1.57) 1.07 (0.91, 1.26) Weight 67.70% 32.30% 100.00% Hypoglycemia, EPY b 33% lower risk with GLP-1 RA (P <.05) 2-4 Relative Risk (95% CI) Weight 0.70 (0.55, 0.90) 0.14 (0.01, 2.65) 0.37% 0.65 (0.50, 0.83) 50.42% 49.21% 0.67 (0.56, 0.80) 100.00% I 2 = 0.0% 0.008 1 4.9 Favors GLP-1 + basal-bolus insulin Δ Weight, kg a 5.66 kg more weight loss with GLP-1 RA (P <.05) 2-4 I 2 = 98.7% Favors basal-bolus insulin Weighted Mean Difference (95% CI) -4.60 (-5.33, -3.87) -1.50 (2.06, -0.94) -11.07 (-12.59, -9.55) -5.66 (-9.80, -1.51) Weight 33.66% 33.81% 32.53% 100.00% -10-8 -6-4 -2 0 2 4 6 8 10 Favors GLP-1 + basal-bolus insulin Favors basal-bolus insulin a Baseline to the end of the intervention; b Any hypoglycemic episode, as defined by the trial. Eng C, et al. Lancet. 2014;384:2228-2234. Diamant M, et al. Diabetes Care. 2014; 37:2763-73. Rosenstock J. et al. Diabetes Care. 2014:37:2317-25. Shao H, et al. Diabetes Metab Res Rev. 2014:30:521-529.
What can we expect when combining a GLP-1 RA and a basal insulin in one pen? Efficacy Side effects HbA 1c FPG PPG WEIGHT HYPOGLYCAEMIA NAUSEA GLP-1 RA monotherapy Basal insulin GLP-1 RA/insulin combined FPG, fasting plasma glucose; GLP-1 RA, glucagon-like peptide-1 receptor agonist; PPG, postprandial glucose
Fixed-Ratio Combination of basal insulin + GLP-1 agonists in clinical practice Indicated in T2DM not controlled on basal insulin or GLP-1 agonist therapy alone 0.036 mg lira/1 unit degludec 0.33 ug lixi/1 unit glargine U100 Weekly titration Max dose Degludec 50 units Liraglutide 1.8 mg Max dose Glargine 60 units Lixisenatide 20 μg
Mean HbA 1c (%) Real-world observational study of patients switching to degludec/liraglutide fixed ratio combination 9.5 Change in HbA 1c over 6 months 9.0 8.9% 8.5 8.5% 8.6% 8.3% 8.3% 8.3% 8.0-0.9%* -1.6%* -1.0%* -0.9%* -0.7%* -0.6%* 7.5 7.6% 7.3% 7.5% 7.4% 7.6% 7.6% 7.0 6.5 Overall (n=566) Non-injectable therapy (n=112) GLP-1RA ±OAD (n=57) Basal ±OAD (n=109) Insulin MDI ±OAD (n=153) Insulin & GLP-1RA ±OAD (n=135) *p<0.0001. Data based on effectiveness analysis set n, number of patients with data at both time points; GLP-1 RA, glucagon like peptide-1 receptor agonist; OAD, oral antidiabetic drugs; MDI, multiple dose insulin injection Price et al. ADA 2017;988-P.
Concentrated Regular Insulin U500
Indication Improve glycemic control in adults and children with diabetes mellitus requiring > 200 units of insulin per day
Regular insulin U500 meta-analysis 0 11.3% 9.6% 9.8% 10.0% 9.9% 9.4% 10.1% 9.1% 9.5% Baseline A1C -0.5-1 -1.5-2 -1.76-1.1-1.4-1.5-1 -1.8-1.59-2.5-3 -2.2-2.5 Mean TDD at baseline 219-391 units Meant change in TDD 52 units Mean weight change 4.4 kg -3.5-3.29 Garg Neal Wafa Nayyar Davidson Dailey Boldo Ziesmer Quinn Overall Reutrakul S, et al. J Diab Science Tech 2012; 6(2): 412-420
Mean Serum IRI Concentration (pmol/l) Glucose Infusion Rate (mg/min) PK/PD Profiles for Regular U-500 vs U-100 Human Insulin Regular U-100 Regular U-500 5x more concentrated ⅕ the volume 1400 1200 1000 800 100-Unit Dose 1000 800 600 100-Unit Dose 600 400 200 400 200 0 0 0 4 8 12 16 20 24 Time (hours) 0 4 8 12 16 20 24 Time (hours) de la Peña A, et al. Diabetes Care. 2011;34:2496-2501.
Regular U-500 Insulin Use pen or U500 syringe to administer Can inject BID or TID BID = 60% / 40% TID = 40% / 30% / 30% = 100 U of U-100 insulin in a U-100 insulin syringe (100 unit markings) 100 U of U-500 insulin in a U-500 insulin syringe (20 unit markings) This shows the same dose (actual U) (1) Humulin R U500 PI. 2016. (2) Eli Lilly and Company. Humulin R U-500 KwikPen. 2016. Available from: http://www.humulin.com/assets/pdf/pp_hm_us_0397_u-500_patient_starter_brochure.pdf
Example of conversion to Regular U500 46 y/o on aspart insulin 40 U with meals and glargine U100 insulin 80 U BID TDD = 280 U per day or 2.3 U/kg/day 120 kg Regular U500 BID (60/40): 168 U in AM and 112 U before dinner Regular U500 TID (40/30/30): 112 U in AM, 84 U at lunch & dinner
Summary Longer-acting basal insulin formulations have similar A1C lowering effect, but lower risk of overnight hypoglycemia More flexible dosing during the day For patients whose A1C remains elevated on > 0.5 U/kg/day, consider adding prandial coverage Faster-acting insulin preparations improve post-prandial hyperglycemia in select individuals Fixed-ratio combinations offer improved glycemic control with weight benefit and low hypoglycemia risk In individuals on > 200 U of insulin a day, consider U500 (probably to improve adherence)