Type 1 Diabetes and Insulin Management in 2020

Irl B. Hirsch, MDUniversity 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 glucose, 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

Insulins: 1950s – 1970s• 1951: addition of zinc at different concentrations without protamine:

semi-lente, lente, ultralente insulins

1962

T1D: 1950s-1960s: with longer-acting insulins most with T1D

treated with one shot/day assessed with urine glucose

testing

1960s-1970s: Jackson and Guthrie advocate for twice daily injections

to better control T1D

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 insulin lispro, 2000 insulin aspart, 2008 insulin glulisine, 2018

FiAsp• 2001 insulin glargine,, 2005 insulin detemir, 2015 insulin degludec

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

Biosimilar 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 biosimilars 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

• Pharmacokinetics (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

• Pharmacodynamics (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 hoursB) 3 hoursC) 4 hoursD) 5 hoursE) 6 hours

Given in the typical doses of 0.1-0.2 units per injection

4

5Se

rum

insu

lin le

vels

(n

g/m

L)

Time (hours)

Insulin Lispro

3

2

1

0 1 2 3 4 5 6 7 8 9 10 11 120

Regular Human Insulin R

Lispro vs Regular (PK)

Diabetes 43: 396-402, 1994

800700600500400300200100

0

Glucodynamic Principles (Analogue Pearl): Prandial Insulin: not as rapid acting as we thought

GlucoseInfusion Rate(mg/kg•min)

0.2 IU/kg SQTime (minutes)

Insulin AspartRegular Insulin

0 120 240 360 480 600

Euglycemic Clamp Profiles

Diabetes Care 1999;22:1501-1506

What About Ultra-Fast-Acting Insulin Analogues To Minimize Hypoglycemia?

0

2

4

6

8

10

12

0 50 100 150 200 250 300 350 400

PharmacodynamicsAfrezza 4 Units

Afrezza 12 Units

Afrezza 48 Units

Afrezza

Fast-Acting Aspart(nicotinamide, L-arginine, aspart)

While theoretically the use of a faster insulin, both “on” and “off” should

reduce hypoglycemia risk, there is no evidence our current SC insulins result in

less hypoglycemia in T1D; what about pulmonary insulin?

Pulmonary Inhaled Insulin vs. Aspart

23

“Compliant” = taking supplemental pulmonary insulin after meal when CGM trends up after dating

Diabetes Tech Thera 2018;20:639-647

54.7

28.8

11.5

30.2

10.1

2.9

31.7

8.6

2.9

0

60

Time in Hypoglycemia <70 mg/dL Time in Hypoglycemia <60 mg/dL Time in Hypoglycemia <50 mg/dL

Tim

e in

Min

Aspart Afrezza Non-Compliant Afrezza Compliantn=34 n=7 n=15

Current and Emerging Basal InsulinsBasal insulins

Human insulins (intermediate acting)

NPH

Analogues (long acting)

U-100 glargine

Detemir

Biosimilar glargine

Analogues (ultralong acting)

U-300 glargine

Degludec

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?

TSA Lines

SeattleTraffic

EPIC

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 DifferentGlargine Doses Injected into Abdomen

1.5 units/kg 2.0 units/kg0.5 units/kg

placebo

1.0, 1.5, and 2.0 units/kg > GIR than 0.5 units/kg, but not greater than each other!

1.0 units/kg

Wang Z, Hedrington MS, Joy NG, et al. Diabetes Care. 2010;33:1555-1560.

Diabetes Care 2007; 30:2447-2452.

PK/PD Glargine vs. Detemir

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(Analogue and human insulin)

PEARLS

PK/PD U100 and U300 glargine

33

• 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 U100 glargine!

NPH Insulin in 201645 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

9 × 2 IU1 × 18 IU

10

8

6

4

2

00 1 2 3 4 5 6 7 8

GIR

, mg/

kg/m

in

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.

70

60

10

20

30

40

50

Insu

linCo

ncen

trat

ion

–U

/ml

degludec 40 U (not given)

12 hrs 24 hrs 36 hrs 48 hrs

Degludec (stopped 24 hours before)

Pump startPump (100%)

Total Basal Insulin (100% pump basal)

Remember, this is PK, not PD, so insulin action will be much longer than this!

70

60

10

20

30

40

50

Insu

linCo

ncen

trat

ion

–U

/ml

degludec 40 U

12 hrs 24 hrs 36 hrs 48 hrs

Degludec (stopped 24 hours before)

Pump start

Based on the PK and without clinical data, it appears stopping the degludec 48 hours before starting

pump and reducing basal for 50% for the first 24 hours, while not perfect, is a reasonable way to do

this transition

Pump (50%)

Total Basal Insulin (50% pump basal)

(not given)

70

60

10

20

30

40

50

Insu

linCo

ncen

trat

ion

–U

/ml

degludec 40 U (Given on day of pump start)

12 hrs 24 hrs 36 hrs 48 hrs

Degludec

Pump startPump (50%)

Total Basal Insulin (50% pump basal)

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.