Insulin Insights for Type 2 Diabetes Disclosure

10/12/2020

Vijay Shivaswamy, MBBS Associate Professor Division of Diabetes, Endocrinology, and Metabolism The University of Nebraska Medical Center/ Nebraska Medicine VA Nebraska-Western Iowa Health Care System

Disclosure

 Site-PI for Clinical trials funded by Novo Nordisk, and KOWA Pharmaceuticals

1 10/12/2020

Not a way to protect oneself from COVID19

Objectives

 Evaluate type 2 diabetes treatment options available for intensifying therapy beyond oral anti-hyperglycemic agents  Identify current barriers to the use of insulin therapy and provide strategies to overcome those barriers  Develop skills for calculating patients’ initial insulin dosage and titrating insulin dosages based on individualized glycemic targets

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Question

What is the most common reason to resist starting insulin in a T2DM patient ?  Feelings of failure  Fear of hypoglycemia  Fear of weight gain  Fear of needles  Insulin causes complications

Question

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Therapeutic Intensification Insulin inertia

Therapeutic inertia -intensification

 Educate progressive nature of diabetes  Avoid using insulin as a threat  Injectable agent (GLP-1 or insulin) after oral agents are done  Do not delay intensification of Rx if not meeting goals  Most patients who need an injectable medication, GLP-1 RA is preferred to insulin.  Re-eval q 3-6 months and adjust

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Therapeutic inertia -insulin therapy

 Misconceptions of insulin therapy  Lack of experience with managing insulin regimens  Cost  Lack of time/ resources to optimize insulin use

Overcoming therapeutic inertia-insulin

Insulin pens Cost Barrier  Great satisfaction  Consider human insulins (NPH/regular)-cost concerns,  Increases likelihood of taking relaxed A1c goals insulin Involve your local diabetes educator  Vial and Syringe  Great portability

 Less reported pain

 Social acceptability

 Better accuracy

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Current Insulin Options

Type Basal Insulins Prandial Insulins Premixed Insulins Human U-100 NPH U-100 regular human insulin U-100 70/30 RHI U-500 regular human insulin Technosphere inhaled insulin

Analog U-100 glargine U-100 lispro U-100 50/50 lispro U-100 glargine equivalent U-100 lispro-aabc U-100 70/30 aspart U-100 detemir U-100 aspart U-100 75/25 lispro U-100 degludec U-100 glulisine U-100 70/30 U-200 degludec U-200 lispro degludec/aspart U-300 glargine

• Analog insulins are associated with less hypoglycemia than human insulins, although these differences are not always statistically significant

Singh SR, et al. CMAJ. 2009;180:385-397. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. FDA. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm.

Insulin Concentrations

Concentration Units/mL Units/vial Units/pen 1000 300 U-100 100 (10 ml per vial) (3 mL/pen) 600 U-200 200 Not available in vials (3 mL/pen) 450 U-300 300 Not available in vials (1.5 mL/pen) 10,000 1500 U-500 500 (20 ml/vial) (1.5 mL/pen)

• Insulin pens significantly reduce the risk of dosing errors and hypoglycemic events • Pens completely eliminate the need for converting doses based on the volume of insulin injected • Dosing errors with U-500 insulin vials are common and dangerous but can be avoided with newly available pens – 5-fold higher insulin dose relative to the same volume of a U-100 insulin 12

Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. Newton C, et al. AACE Annual Meeting. 2013 [abstract 271]. Segal AR, et al. Am J Health Syst Pharm. 2010;67:1526-1535.

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Question

Mrs. K is a 53 yo female with type 2 diabetes and is on metformin, empagliflozin and dulaglutide (A1c is 8.2%, down from 10.4%,a year ago). She is agreeable to start basal insulin. What is the initial dose of the basal insulin?

A. 10 units

B. 0.2 u/kg

C. 1 unit/kg

D. 3 units/kg

E. A or B

American Diabetes Association Dia Care 2020;43:S98-S110

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Question

A. 10 units

B. 0.2 u/kg

C. 1 unit/kg

D. 3 units/kg

E. A or B

Question

Mrs. K started 10 units insulin glargine. FPG goal is < 130 and she plans to start SMBG. What instructions would you give to Mrs. K to titrate the insulin ?

A. Decease by 2 units every 3 days

B. Increase by 2 units every 3 days

C. Increase by 4 units every 7d

D. Increase by 8 units every 14 d if FPG > 180

E. Only Mrs. K’s provider should be titrating the dose.

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Titration –Basal insulin

 Increase 2 units every 3 days to reach FPG without hypoglycemia  Continue regimen and check A1c q3 mo.  If hypoglycemia, address cause, reduce dose by 10-20%, and reassess  Once you start insulin, TITRATE

Diabetes care 2010;33:1176-1178

Patient self-titration is effective

Melanie Davies et al. Dia Care 2005;28:1282-1288

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Question

Mrs. K started 10 units insulin glargine. FPG goal is < 130 and she plans to start SMBG. What instructions would you give to Mrs. K to titrate the insulin ?

A. Decease by 2 units every 3 days

B. Increase by 2 u every 3 days

C. Increase by 4u every 7d

D. Increase by 8 u every 14 d if FPG > 180

E. Only Mrs. K’s provider should be titrating the dose.

Summary

 3 mo f/u of Mrs. K  Metformin, Dulaglutide, empagliflozin, and Insulin glargine 28 units QHS A1c 6.8%  FPG 118  No s/s hypoglycemia

10 10/12/2020

This one is for all the parents helping their kids with remote learning/home schooling

Case Study

 Mr. L  50 yo man  DM 10 yrs.  H/o CAD s/p CABG  BMI 43  A1c 9.5, FPG 122 (14 day average), 2h PPG 220-250.  No reported hypoglycemia.  Metformin, acarbose, empagliflozin, insulin degludec 35 units QHS (which he is taking inconsistently-3-4 days/week)  Struggles to lose weight  Exercises 3/week

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Question

What is the next best Rx to lower his A1c ?  GLP-1 RA  Basal insulin/Glp-1RA combination  Premixed insulin  Basal/bolus insulin  Any of the above

GLP-1 or insulin ?

GLP-1 RA Insulin  Patient preference  High A1c (> 11%)  A1c lowering  s/s catabolism (weight  Frequency of injection loss, polyuria, polydipsia)  Established CVD risk benefit  ? Type 1 possibility

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Benefits of Basal Insulin/GLP-1 RA Fixed Ratio Combinations

 Target both FPG and PPG to improve glycemic control (vs individual components)  No individual risks of hypoglycemia vs basal insulin alone (despite improved glycemic control)  Weight neutrality or loss  Slow up-titration reduces gastrointestinal effects vs GLP-1 RA alone  A simplified regimen—reduced complexity vs premixed and basal bolus regimens may increase patient adherence

FPG, fasting plasma glucose; GLP-1 RA, glucagon-like peptide-1 receptor agonist; PPG, postprandial plasma glucose. 1. Rosenstock J, et al. Diabetes Care. 2016;39:2026-2035. 2. Aroda VR, et al. Diabetes Care. 2016;39:1972-1980. 3. Gough S, et al. Lancet Diabetes Endocrinol. 2014;2:885-889. 4. Buse JB, et al. Diabetes Care. 2014;37:2926-2933.

Fixed-Ratio Combinations of Basal Insulin and GLP-1 RA

• iGlarLixi 100/33 • iDegLira 100/3.6 • Insulin glargine and lixisenatide injection • Insulin degludec and liraglutide injection • Approved by FDA November 2016 • Approved by FDA November 2016 • Indication: Adults with T2D inadequately controlled on diet and • Indication: Adults with T2D inadequately controlled on diet and exercie exercise • 1 unit contains: • 1 unit contains: • 1 U insulin glargine and • 1 U insulin degludec and • 0.33 mcg lixisenatide (a GLP-1 RA) • 0.036 mg liraglutide (a GLP-1 RA) • Administered SC once daily • Administered SC once daily • Starting dose: 15 (15 U insulin glargine and 5 mcg • Starting dose: 10 or 16 units (10 or 16 U insulin degludec and lixisenatide) 0.36 or 0.58 mg liraglutide) • SoloStar pen • FlexTouch pen

FDA, US Food and Drug Administration; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SC, subcutaneous; iDegLira, insulin degludec and liraglutide; iGlarLixi, insulin glargine and lixisenatide; T2D, type 2 diabetes. 1. Soliqua™ 100/33 (insulin glargine and lixisenatide injection). Prescribing Information, Sanofi-Aventis US. November 2016. 26 2. Xultophy® 100/3.6 (insulin degludec and liraglutide injection). Prescribing Information, Novo Nordisk. November 2016.

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Soliqua Xultophy  Maximum dose is 60 units

Glucose Control With iGlarLixi

Add-on to OA, Add-on to Basal Insulin Insulin-Naive ± OAs 30 Weeks1 30 Weeks2

N 1070 736

Lixi Glar* iGlarLixi Glar* iGlarLixi Treatment

Baseline A1C (%) 0 8.1 8.1 8.1 8.5 8.5

-0.5 -0.6 -1 -0.9 A1C (%) -1.1  -1.5 -1.3 P<0.0001 -1.6 -2 P<0.0001 P<0.0001

Per protocol maximum dose: 60 units/day. A1C, glycated hemoglobin; iGlarLixi, insulin glargine and lixisenatide; OAs, oral agents. 1. Rosenstock J, et al. Diabetes Care. 2016;39:2026-2035. 2. Aroda VR, et al. Diabetes Care. 2016;39:1972-1980.

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Glucose Control With iDegLira

Add-on to OA, Add-on to Basal Insulin Insulin-Naive ± OAs 26 Weeks1 26 Weeks2

N 1663 413

Lira iDeg iDegLira iDeg* iDegLira Treatment

Baseline A1C (%) 0 8.3 8.3 8.3 8.8 8.7

-0.5

-1 -0.9

A1C (%) -1.5 -1.3 -1.4  -2 -1.9 -1.9 NI P<0.0001 -2.5 P<0.0001 S P<0.0001

*Per protocol maximum dose: 50 units/day (no maximum dose of degludec alone was specified in the insulin naïve trial). A1C, glycated hemoglobin; iDeg, insulin degludec; iDegLira, insulin degludec and liraglutide; Lira, liraglutide; NI, noninferior; OAs, oral agents; S, superior. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-893. 2. Buse JB, et al. Diabetes Care. 2014;37:2926-2933 .

Question

What is the next best Rx to lower his A1c ?  GLP-1 RA  Basal insulin/Glp-1RA combination  Premixed insulin  Basal/bolus insulin  Any of the above

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Case Study

Mr. L now has A1c 8.2, FPG < 120, PPG 180-200 On basal + GLP-1RA. What next ? A. Increase basal insulin B. Split basal insulin C. Basal premixed BID D. Add prandial to evening meal E. C or D

Prandial insulin

If A1c > goal despite optimizing basal insulin titration and FPG at goal  Add prandial with biggest meal  4u or 10% of basal dose  A1c <8%, consider lowering TDD by 4u or 10%  Titrate by 1-2 units or 10-15% twice weekly until goal

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Prandial insulin-titration  ≤10 units – Increase by 1 unit

 11 to 20 units – Increase by 2 units

 >20 units – Increase by 5 units (or more, depending on patient insulin resistance, meal size, and content)

 Carbohydrate counting- Insulin to carbohydrate ratio

 SMBG before and 2 h post OR CGMS

 Address hypo cause

 Reduce by 10-20%

 Stepwise addition of prandial insulin  better patient acceptance, lower hypo than full basal/ bolus

Premixed insulin

Benefits Disadvantages

 Simple  Higher risk of hypoglycemia and weight gain  Convenient  Less flexibility  Basal/bolus in one medication

Initiation/ titration  Insulin naïve patients-10-12 units or 0.3 u/kg  Existing basal/ bolus unit to unit conversion  2/3 AM and 1/3 PM OR 1/2 AM and 1/2 PM  For ex: 30 units basal 20 units of 70/30 with breakfast and 10 units with dinner  Titration: 1-2 unit or 10-15% once or twice weekly until goal

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Percentage of subjects achieving HbA1c target values at the end of the study

Philip Raskin et al. Dia Care 2005;28:260-265

Case Study

Mr. L now has A1c 8.2, FPG < 120, PPG 180-200 On basal + GLP-1RA. What next ? A. Increase basal insulin B. Split basal insulin C. Basal premixed BID D. Add prandial to evening meal E. C or D

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Summary

 Intensifying therapy to meet glycemic targets can reduce microvascular complications  When prandial insulin is necessary, start with one dose of prandial insulin with main meal and titrate as needed to prandial insulin with all meals  If less complex therapy is needed, switch basal to premixed insulin

Inpen

 a reusable injector pen plus an intuitive smartphone interface  smart insulin delivery.

 InPen was cleared by the FDA in 2016 and launched in December 2017.

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V go

 Simplified Insulin Delivery Worn Like a Patch

 Releases a steady rate of rapid-acting insulin for basal control

 Delivers prandial insulin at the click of a button

 Patients on multi-dose insulin injections and not well controlled

 Basal: A spring-activated mechanism delivers insulin at a continuous preset basal rate.

 Bolus: A manually activated mechanism delivers insulin for on-demand bolus insulin dosing at mealtimes with simple clicks.

1. Harrison HC, Everitt B, Nikkel C. Poster: The Impact of utilizing a novel insulin delivery device in patients with type 2 diabetes. Presented at ACCE.

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No preface needed

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Newer/concentrated insulins

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Case

62 yo obese man; 8 yr. h/o T2DM and CVD . Oral meds and 90 units U100 glargine qhs. FBS 112-130, A1c 7.2 %. Reports 1-2 episodes of nocturnal hypoglycemia/ week. Options ?

A. Decrease dose of U100 Glargine

B. Switch to U300 Toujeo

C. Switch to Degludec (Tresiba) (U100 or U200)

D. No changes

E. B or C

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Insulin Degludec 200 unit/mL Is Noninferior to Insulin Degludec 100 unit/mL in Patients With T2DM

Insulin degludec 100 unit/mL (n=187) Insulin degludec 200 unit/mL (n=186) HbA1c (%) HbA1c

Noninferior

Weeks

N Engl J Med. 2017 Aug 24;377(8):723-732.

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Insulin Glargine 300 unit/mL (basal) Nonbioequivalent to insulin glargine 100 unit/mL

Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes, Volume: 17, Issue: 9, Pages: 859-867, First published: 30 April 2015, DOI: (10.1111/dom.12485)

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Case

62 yo obese man; 8 yr. h/o T2DM and CVD . Oral meds and 90 units U100 glargine qhs. FBS 112-130, A1c 7.2 % Reports 1-2 episodes of nocturnal hypoglycemia/ week. Options ?

A. Decrease dose of U100 Glargine

B. Switch to U300 Toujeo

C. Switch to Degludec (Tresiba) (U100 or U200)

D. No changes

E. B or C

Case

62 yo obese veteran with type 2 diabetes, metformin 1g BID, glargine (U-100) 80 u BID, aspart 35 units BID. A1c 11%. No hypos. Next best step ?

 Replace glargine U-100 with U-300

 Replace glargine U-100 with U-200 degludec

 Replace glargine + aspart with U-500

 Replace aspart with U-200 Humalog

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 Humulin R U-500 is a concentrated human insulin indicated to improve glycemic control in adults and children with diabetes mellitus requiring more than 200 units of insulin per day.

TDD= 200 units, TID =

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U-500R Safety

 Hypoglycemia can occur suddenly, and symptoms may vary among individuals and be different or less pronounced under certain conditions  Severe hypoglycemia may develop as long as 18 to 24 hours after an injection of U-500R.

U-500=500 units/mL; U-500R=human regular U-500 insulin BD is a registered trademark of Becton, Dickinson and Company Humulin R U-500 [US Package Insert]. Indianapolis, IN: Eli Lilly and Company, 2016

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Case

62 yo obese veteran with type 2 diabetes, metformin 1g BID, glargine (U-100) 80 u BID, aspart 35 units BID. A1c 11%. No hypos. Next best step ?

 Replace glargine U-100 with U-300

 Replace glargine U-100 with U-200 degludec

 Replace glargine + aspart with U-500

 Replace aspart with U-200 Humalog

Summary of Concentrated Insulins

♦ Commonly available insulin concentrations today include 100, 200, 300, and 500 unit/mL ♦ Understanding whether concentrated insulins are bioequivalent or nonbioequivalent to their 100 unit/mL counterpart is essential ♦ U-500R is indicated for patients with diabetes mellitus requiring >200 units of insulin per day ♦ Do not use U-500 insulin with U-100 insulins

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Inhaled Insulin

 Inhaled administration  Rapid-acting insulin  Peak levels achieved in ~15 minutes

Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212.

Insulin experienced patients

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Safety Considerations with Inhaled Insulin

• Contraindicated in asthma, COPD, and other chronic lung diseases • Perform spirometry to assess lung function before initiating inhaled insulin, after 6 months of therapy, and annually thereafter, even in the Lung disease absence of pulmonary symptoms • Do not use in patients with active lung cancer and use with caution in patients with a history of lung cancer or those at risk for lung cancer

• Observe for signs and symptoms of fluid retention or heart failure, Heart failure especially when used with TZDs

Hypoglycemia • Increase frequency of glucose monitoring

Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

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T2DM uncontrolled on oral medications/ Prandial lifestyle insulin

Special considerations: 1) U200 degludec/U300 glargine (if hypoglycemia GLP-1RA on U100 glargine) 2) Humalog U200-large volume U100 rapid acting 3) Humulin U500 if TDD > 200 units/day and Convert to uncontrolled Premix 4) Ultra-rapid acting insulin 4) Inhaled insulin-needle phobia, lipohypertrophy, Basal insulin 5) Inpen: automated bolus calculators 5) Insulin pumps-V-GO. NPH and short/rapid acting

Remember: INITIATE and TITRATE !

Conclusion

 Type 2 diabetes mellitus is a progressive disease  Recognize and overcome therapeutic inertia  Consider GLP-1 RA, basal insulin, prandial/premixed insulins, in that order, for acceptable intensification of therapy  Inhaled insulin is an option, but not widely used  Higher concentrations of insulin are available for patients with very high insulin resistance or experiencing hypoglycemia on U-100 insulin.  Refer to specialist: Type 1 DM, need for concentrated insulins, insulin pump, CGM, A1c > 9 despite optimizing treatment

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