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Home , Insulin glargine

and Management in 2020

Irl B. Hirsch, MD University of WA School of Medicine Seattle, WA Dualities

• Consulting: Abbott Diabetes Care, Bigfoot, Roche • Research funding: Medtronic Diabetes “Insulin was discovered in 1921 by Fred Banting and Charles Best. In a generous gesture that unfortunately didn’t start a trend, they sold the patent for a dollar so that cheap insulin would quickly become available. It worked like a charm: within two years, Eli Lilly had sold 60 million units of its purified extract of pig and cow pancreas” Von Wartberg, L: Diabetes Health, May 23. 2007 Dogs 92 and 409, blood and urine , August 11, 1921 Insulin Toronto Iletin, Eli Lilly, 1920s

Initial insulin from Lilly: potency varied up to 25% per lot; the development of isoelectric precipitation led to a purer and more potent animal insulin, decreasing variation between lots to 10% (Rosenfeld L. Insulin: discovery and controversy. Clin Chem. 2002;48:2270– 88) The History of NPH Insulin

• Hagedorn and Krogh obtained the rights for insulin from Banting and Best in 1923 to form Nordisk Insulin laboratorium, a non-profit company • Hegedorn and Jenssen discovered that the effects of injected insulin could be prolonged by the addition of protamine obtained from the semen of river trout • Insulin added to the protamine, pH brought to 7.0, and protomine zinc insulin was introduced in 1936 (24-36 hours) • 1946: crystals of protamine formed and when mixed with insulin formed NPH, introduced in 1950 • Shortly afterwards Eli Lilly introduced an NPH insulin : 1950s – 1970s • 1951: addition of zinc at different concentrations without protamine: semi-lente, lente, ultralente insulins

T1D: 1950s-1960s: with longer- 1960s-1970s: Jackson and Guthrie acting insulins most with T1D advocate for twice daily injections 1962 treated with one shot/day to better control T1D assessed with urine glucose testing

Pre-1970s insulin: thousands of impurities per pmol/L; resulted in allergies and lipoatrophy; 1974-purified insulins at 1 pmol/L 1982: Human Insulin The Introduction of Insulin Analogues • 1996 , 2000 , 2008 , 2018 FiAsp • 2001 ,, 2005 , 2015 We’ve Come a Long Way…or Have We?

• WHO global action plan for the prevention and control of non-communicable diseases, 2013-2020 • Target: “an 80% availability of the affordable basic technologies and essential medicines, including generics, required to treat major non- communicable diseases in both public and private facilities.”

How do we do? Global Insulin Rationing T1International 2016 Survey (IDF 2019) • 1478 respondents in 90 countries • Globally: 18% ration due to cost • US: 26% ration (N=627) compared to 6% of the other high - income countries (N=525 respondents) • Low- and mid-income countries: 10.9% insulin rationing (N=256)

Who would have thought low- and mid-income countries made the 2020 WHO target for insulin access written in 2013, yet the US has twice as much insulin access challenges than the poorest countries in the world. How should you feel? 35-64 year-olds

18 to 34-year-olds have an uninsured rate of 21.6% https://news.gallup.com/poll/246134/uninsured-rate-rises-four-year-high.aspx accessed November 18 2019 Although the Road is Far From Perfect

For Those Who Can Afford It Insulin Therapy Continues to Improve Released November 26, 2019 vs. Interchangeable

• The biological product is biosimilar to a reference product based upon data derived from analytical studies demonstrating that the proposed biosimilar is highly similar to the reference product, animal studies, and a clinical study or studies (including the assessment of immunogenicity and PK or PD) • To be interchangeable, biosimilarity to the reference product needs to be shown, and also to demonstrate that the biological product can be expected to produce the same clinical result as the reference product in any given patient. “Interchangeable” or “interchangeability” mean that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product What About “Follow-On Biologics”?

• Designation of insulins prior to FDA guidance on and interchangeables • The biosimilars Basaglar (glargine) and Admelog (lispro) are not interchangeable with Lantus and Humalog respectively • What about generics? • Large molecules derived from living organisms or other advanced methods- it’s almost impossible to make an exact replica of the original drug • “Generic” lispro and aspart are exact replicas of Humalog and Novolog since made by the same companies (Lilly and Novo) Understanding PK vs. PD

• (PK): the time course of the circulating concentration of insulin that results from a subcutaneous injection or other method of delivery. Can be measured by measuring insulin levels or specific level of analogue • (PD): the time course of the effect on blood glucose concentration. Best understood with a euglycemic clamp study What Is Duration of Action of Our Current Rapid-Acting Analogues?

A) 2 hours B) 3 hours Given in the typical doses of 0.1-0.2 units per C) 4 hours injection D) 5 hours E) 6 hours Lispro vs Regular (PK)

5

4 Insulin Lispro Regular Human Insulin R 3

2 (ng/mL) 1 Serum insulin levels 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hours)

Diabetes 43: 396-402, 1994 Glucodynamic Principles (Analogue Pearl): Prandial Insulin: not as rapid acting as we thought Euglycemic Clamp Profiles 800 700 Insulin Aspart 600 Glucose Infusion Rate 500 (mg/kg•min) 400 300 200 100 0 0 120 240 360 480 600 Time (minutes) 0.2 IU/kg SQ

Diabetes Care 1999;22:1501-1506 What About Ultra-Fast-Acting Insulin Analogues To Minimize ? Fast-Acting Aspart (nicotinamide, L-arginine, aspart) While theoretically the use of a faster Afrezza insulin, both “on” and “off” should

12 Pharmacodynamicsreduce hypoglycemia risk, there is no 10 evidenceAfrezza our 4 Unitscurrent SC insulins result in 8 less hypoglycemiaAfrezza 12 Units in T1D; what about 6 Afrezza 48 Units 4 pulmonary insulin? 2 0 0 50 100 150 200 250 300 350 400 Pulmonary Inhaled Insulin vs. Aspart “Compliant” = taking supplemental pulmonary insulin after meal when CGM trends up after dating 60 Aspart Afrezza Non-Compliant Afrezza Compliant 54.7 n=34 n=7 n=15

31.7 30.2 28.8 Timein Min 11.5 10.1 8.6 2.9 2.9 0 Time in Hypoglycemia <70 mg/dL Time in Hypoglycemia <60 mg/dL Time in Hypoglycemia <50 mg/dL

23 Diabetes Tech Thera 2018;20:639-647 Current and Emerging Basal Insulins

Basal insulins

Human insulins Analogues (long acting) Analogues (ultralong acting) (intermediate acting)

NPH U-100 glargine U-300 glargine

Detemir Degludec

Biosimilar glargine Follow-on biologic glargine With Basal Insulin, Like Many Aspects of Our Lives, We Are Promised Incremental Improvements But is everything we are told truly incremental improvements?

EPIC

Seattle Traffic TSA Lines Questions

• Are the newer basal insulins incrementally beneficial? • Are the newer basal insulins cost-effective? • How to deal with these newer insulins in common situations such as surgical procedures, inpatient conversion when not on formulary, transitioning to insulin pump therapy? Glucose Infusion Rates (GIRs) for Different Glargine Doses Injected into Abdomen 1.0, 1.5, and 2.0 units/kg > GIR than 0.5 units/kg, but not greater than each other! 1.5 1.0 units/kg units/kg 0.5 units/kg 2.0 units/kg

placebo

Wang Z, Hedrington MS, Joy NG, et al. Diabetes Care. 2010;33:1555-1560. PK/PD Glargine vs. Detemir

Diabetes Care 2007; 30:2447-2452. Clinical Case: Hypoglycemia Unawareness

• 40 y/o woman with T1D X 35 years, had to stop CSII due to poor insulin absorption (had been on CSII X 28 years) • SEVERE gastroparesis with failed gastric stimulator • Wears Dexcom, takes glargine and lispro. Have tried regular insulin for prolonged gastric emptying but not of help • Dexcom low alert at 80 mg/dL (4.4 mmol/L), A1c 7.8%, mean/sd/CV 174/60/36 • What to do? Switching to Degludec: Real World Experience • N=556 w T1D, 611 w/T2D switched to degludec over 12-months

JCEM 2019;104:5977-5990 Once in Steady State, Degludec is Very Flat

Clin Drug Investig 2013; 33:515-521 INSULIN PEARLS (Analogue and human insulin) PK/PD U100 and U300 glargine

TWO pearls: • 1. U300 glargine consistently has a longer duration than U100 glargine and BID dosing is not required 2. Package insert from Study A (registration trial): “Patients treated with TOUJEO used 17.5% more basal insulin than patients treated with LANTUS.” 1. So: understand you will require higher doses of U300 glargine than 33 U100 glargine! NPH Insulin in 2016 45 y/o man who still had insulin lispro and a few CGMs from 2015. Deductible is $4000 and can’t afford list price of insulin glargine (let alone insulin degludec), so he simply used NPH instead. His A1c is 6.9%

NPH isn’t so bad if you know how to use it! Pearls for Human Insulin Use in T1D

• It’s ok to use 2020 technology for 1980s insulin! • Use of occasional, personal, or professional CGM to assist best insulin needs and strategies may be helpful • Due to higher rates of hypoglycemia it may be advisable to increase glycemic targets. • Even more so than with insulin analogues, consistency in timing and amount of meal (especially carbohydrate) will benefit overall control in T1D. Pearls for Human Insulin Use in T1D

• Location: abdomen > arms > thigh > buttocks • Generally: R best in abdomen, NPH needs to be given consistently in same location (thighs or buttocks) • Mixing: NPH needs to be mixed well! • “Lag times”: CRITICAL with regular insulin. Usually 20-30 min minimum required to prevent large post-meal spike • SNACKING: often required, especially at bedtime to prevent nocturnal hypoglycemia. • Some patients require a small dose of NPH in AM if using R as prandial insulin, definitely requires some NPH if using RAA

Abbreviations: R, regular insulin; RAA, rapid-acting analogue insulin What About Giving Many Small Doses Instead of One Large Depot (Analogue Pearl)? Insulin Aspart PK/PD: Dispersed Injection vs Single Injection, AP@home Consortium Pharmacodynamics in T1D 10 9 × 2 IU 8 1 × 18 IU

6

4 GIR, mg/kg/min GIR, 2

0 0 1 2 3 4 5 6 7 8 Time, h

Clamp study of 12 patients with T1D. Mader JK, et al. Diabetes Care. 2013;36:780-785. Clinical Dilemma: Transitioning from Degludec to Insulin Pump Therapy • A 29 y/o obese man with T1D decided to begin insulin pump therapy. His current regimen is 40 units of insulin degludec in the morning with premeal insulin aspart. What to do with the degludec, and how to dose the basal insulin? • A. Degludec stop the day before, usual basal insulin via pump • B. Degludec stop the day before, 50% basal insulin via pump • C. Stop degludec the day OF, 50% basal insulin via pump • D. Stop the degludec the day OF, no basal insulin x 24 hours via pump • E. Email Steve Edelman and ask him Why This is So Complicated

• With insulin degludec, based on its PK, the time to reach steady state is consistently between 3 and 4 days • Half-life of degludec is 25 hours • Rule of thumb: after 1 half-life, 50% of steady state is reached; after 2 half-lives, 75% of steady state is reached. Remember, this is PK, not PD, so insulin action will 70 be much longer than this!

U/ml 60

– Total Basal Insulin (100% pump basal) Degludec 50 (stopped 24 40 hours before) Pump (100%) 30 Pump start Concentration 20 Insulin 10

12 hrs 24 hrs 36 hrs 48 hrs degludec 40 U (not given) Based on the PK and without clinical data, it appears stopping the degludec 48 hours before starting 70 pump and reducing basal for 50% for the first 24 hours, while not perfect, is a reasonable way to do

U/ml 60 this transition – Degludec 50 (stopped 24 40 hours before) Total Basal Insulin (50% pump basal) 30 Pump start Concentration 20 Pump (50%) Insulin 10

12 hrs 24 hrs 36 hrs 48 hrs degludec 40 U (not given) 70 Total Basal Insulin (50% pump basal)

U/ml 60 – 50 Degludec 40

30 Pump start Concentration 20 Pump (50%) Insulin 10

12 hrs 24 hrs 36 hrs 48 hrs degludec 40 U (Given on day of pump start) Summary of Pump Therapy for T1D in 2020 • About 30% in US using CSII (60% in T1DEx) but this may change with increase in automated insulin delivery (AID). • By the end of 2020 there could be 3 AID systems available in US Summary of Technology Moving Forward for T1D

• More AID systems in development: Beta Bionics and Bigfoot • CGM is exploding due to improved efficacy and better payer coverage • The biggest change for insulin users may not be AID systems but rather digital pens for insulin use due to the number of people using MDI Conclusions

• The discoverers of insulin would be ashamed if they saw how many parts of the world, particularly the US has made insulin inaccessible for many • For those who can’t afford insulin analogues, human insulin remains an option-particularly if CGM is available. • Newer basal insulins have resulted in less hypoglycemia in clinical trials but have also introduced new challenges with transitions (pumps and inpatient) • Technology is adding further improvements to insulin therapy.