Insulin Therapy for Diabetes: What are our Options and Strategies?

Mona Nasrallah M.D Endocrinology and Metabolism

Annual Conference of the Lebanese Society of Family Medicine September 30, 2017

• Disclosures: None

• Objectives:

• To become familiar with when to start insulin therapy, how to start it, and how to monitor it.

• To overview the currently available insulins, and ADA guidelines

Primary Care Diabetes

http://www.primary-care-diabetes.com

Key concepts

Customize therapy Basal-Bolus concept

Inzucchi et al 2014 ADA EASD

When would you recommend insulin on a patient?

When to start insulin Uncontrolled

glucose despite combination

therapy

Organ dysfunction Liver, kidney, heart

Flexible dosing

Insulin after metformin The GRADE study

Glycemia Reduction Approaches in Diabetes

Expected mid 2020

https://clinicaltrials.gov/ct2/show/NCT01794143

What are some barriers to insulin?

Biased perception of patient : ability to deal with complex regimens, fear of

injections

Lack of time

Technically Cumbersome

No perceived

benefit

No system support

Psychological insulin resistance

Fear of hypoglycemia

Insulin is ‘the end of the

road’

Insulin is ‘the end of the

road’

Biased perception of patient : ability to deal with complex regimens, fear of

injections

Lack of time

Technically Cumbersome

No perceived

benefit

No system support

Fear of hypoglycemia

Psychological insulin resistance

Train your staff Identify

educators

Assign 10-15 minutes to buy them into plan

Be familiar with guidelines Nurse-led algorithm

Automated system reminder

Get to know patient Discussion in clinic

Work with educator DSME is key

Pens

Counsel Judicious

concomitant meds

Dosing and self-titration Newer insulins

Anticipatory guidance in clinic early on in

diabetes course

How to overcome these barriers?

Predictors of successful insulin adherence

• Positive predictors are: – Diabetes nurse specialist support

– The use of a pen device

– Hypoglycemia awareness

– Higher perception of personal control

• Negative predictors are: – Female gender

– Number of injections

– Lower HbA1C

How to start insulin

• Be familiar with insulins

• Be familiar with guidelines ADA/EASD 2017

Question • Compared to NPH insulin, the main advantage

of recombinant insulin analogs detemir, glargine, and deglutec is:

• 1- do not cause weight gain

• 2- cause less nocturnal hypoglycemia

• 3- have a more rapid peak effect

• All of the above

The medical letter 2017

Basal insulins available

Fonseca and Leffert https://learning.freecme.com/attendee/view_program.jsp?programCode=27881P3649EH

Hypoglycemia rates with newer analogs versus glargine U-100

Metaanalysis of phase 3 clinical studies

Prandial insulins available

Fonseca and Leffert https://learning.freecme.com/attendee/view_program.jsp?programCode=27881P3649EH

Insulin type Regular Glulisine Lispro Aspart I-Asp*

Onset 30-60 min

5-15 min 3 min

Peak 2-4 hours

45-75 min 20 min

Effective duration

5-8 hours

2-4 hours 50 mn

* Coupled to arginine and niacinamide

Inhaled insulin

Cost in Lebanon MOPH: basal insulins

ATC Name B/G Ingredients Dosage Form Price

A10AE06 TRESIBA BioTech Insulin degludec - 100IU/ml

100IU/ml Injectable solution

159,501 L.L

A10AE04 BASAGLAR KWIKPEN

BioTech Insulin glargine - 100U/ml

100U/ml Injectable solution

102,518 L.L

A10AE04 LANTUS BioTech Insulin glargine - 100IU/ml

100IU/ml Injectable solution

115,031 L.L

A10AE04 TOUJEO BioHuman Insulin glargine - 300Units/ml

300Units/ml

Injectable solution

131,507 L.L

A10AE01 HUMULIN N U-100

BioHuman Insulin (human) - 100IU/ml

100IU/ml Injectable suspension

23,594 L.L

Note: quantities may not be equal between one product and the other

Cost in Lebanon MOPH: prandial insulins

A10AB04 Name B/G Ingredients Dosage Form Price

A10AB04 HUMULIN R U-100

BioHuman Insulin (human) - 100IU/ml

100IU/ml Injectable solution

23,594 L.L

A10AB04 HUMALOG KWIKPEN

B Insulin lispro - 100IU/ml

100IU/ml Injectable solution

86,481 L.L

A10AB04 HUMALOG KWIKPEN

B Insulin lispro - 200IU/ml

200IU/ml Injectable solution

148,749 L.L

A10AB06 APIDRA SOLOSTAR

BioTech Insulin glulisine - 100IU/ml

100IU/ml Injectable solution

70,606 L.L

A10AB05 NOVORAPID FLEXPEN

BioTech Insulin aspart - 100IU/ml

100IU/ml Injectable solution

80,359 L.L

http://www.moph.gov.lb/en/Drugs/index/3/4848/lebanon-national-drug-index

ADA/EASD

Diabetes Care 2017 40: S1

ADA/EASD (cont)

Diabetes Care 2017 40: S1

Case Scenario: George

• 56 yo white male with a 7-y history of T2DM

• Titrates glargine U-100 with a mean FPG 130-145 mg/dL

• HbA1c 7.8%

• SMBG 2-3 days/week

• Has occasional night sweats and restless sleep at 2-3 am

• Current medications

– Metformin 1000 mg bid

– Pioglitazone 30 mg qAM

– Glargine U-100 65 units qHS • Vital signs: stable; weight 95 kg; BMI 31.0 kg/m2

What considerations do you have?

Case from Fonseca and Laffert

When to Stop Titrating Basal Insulin and Consider Prandial Control Options

The individual is not meeting glycemic targets on basal insulin1-4

and:

HbA1C still not at goal with

0.5 units/kg/d of daily basal

insulin3

HbA1c elevated despite normal FPG with basal

insulin2,3

FPG with basal insulin is within targeted range,

but PPG is persistently

above goal3,4

Further increases in basal insulin

result in hypoglycemia3

1. Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. Alexandria, VA: American Diabetes Association, Inc.; 2004:207-223. 2. American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68. 3. Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379. 4. Davidson MB, et al. Endocr Pract. 2011;17:395-403.

Options for intensifying basal insulin

Basal Insulin Once-daily

Increase Dose/Frequency

+ Oral Agent(s)

+ DPP-4i

+ GLP-1RA

+ SGLT-2i

+ Pioglitazone

+ Prandial Insulin

ADA/EASD

Diabetes Care 2017 40: S1

Insulin and cardiovascular safety

• UKPDS

– Lowering HbA1C to 7 % versus 7.9 % associated with CV benefit after 10 years

• ORIGIN

– glargine

• DEVOTE

– deglutec

Cardiovascular Safety of Insulin Glargine U-100: ORIGIN Study

Composite of MI, Stroke, CV Death Composite of Revascularization or Heart Failure Hospitalization

ORIGIN Investigators. N Engl J Med. 2012;367():319-328.

*12,537 people with increased CV risk plus impaired fasting glucose, impaired glucose tolerance, or T2DM were randomized to insulin glargine U-100 vs standard care. Mean follow-up was 6.2 years.

Absolute rates hypoglycemia 16 versus 5 per 100 pt-years For any hypoglycemia 1.00 versus 0.31 per 100 pt-years For severe nocturnal hypoglycemia glargine vs PBO

Cardiovascular Safety of Insulin Degludec: DEVOTE Study

• 7637 people with T2DM at high CV risk were randomized to standard care plus

– Insulin degludec or

– Insulin glargine U-100

– Target: FPG 71 to 90 mg/dL

• Follow-up ~2 years

• At baseline

– Age (mean): 65.0 y

– HbA1c (mean): 8.4%

– Duration of T2DM (mean): 16.4 y

– 85.2% established CVD or moderate CKD

– 83.9% receiving insulin • 54.8% basal-bolus

Marso SP, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615692.

Absolute rates hypoglycemia 6.25 versus 3.7 per 100 pt-years For any hypoglycemia 1.40 versus 0.65 per 100 pt-years For severe nocturnal hypoglycemia glargine VS DEG

Case scenario: Suha

• 67 year-old woman referred July 2017 by family physician for HbA1C 14 % along with severe hypoglycemia.

• Diabetes since 2006, on OHA for one year, then insulin.

• Breast ca, s/p neoadj chemo then MRM 2010

• Mild DKA 2012, anti-Gad 1.1 (N < 1)

• Hypothyroidism on L-T4

Clinical scenario (cont)

• She had stopped insulin aspart due to severe hypoglycemia and was on basal glargine only 30- 0-0-10

• Her social history/lifestyle: – Works from 4 to 6 AM in the field picking tobacco

leaves, has hefty breakfast at 6 AM, then rests throughout the day.

– Her son can give her the insulin in AM and PM only

• Hypo’s at night and early morning

• Asked her to reduce glargine to 5 in the evening (from 10) and to monitor glucose before breakfast and 2 hours after.

Next step?

• Proposed combination deglutec and aspart (70/30) in the morning with breakfast 25 units

• She starts regimen and puts a 2-week glucose monitoring device

Readings

Opinion?

• Major change in lifestyle again

• Main exertion after breakfast 6 AM -12 noon

• (Now ‘gathering’ the leaves)

• Changes insulin deglutec/aspart to twice daily 16-0-16-0 per scale before meals

• Asked about next lifestyle change?

Case scenario: Nadia

• 77 year-old woman with ovarian adenoca, Stage IV referred by oncologist Oct 2016 for uncontrolled glucose, s/p chemo, on maintenance bevacizumab.

• T2D X 26 years, HbA1C 8.8 %

• SMBG 180-220’s in AM on canagliflozin, gliclazide, and saxagliptin

• Diarrhea with metformin, severe UTI

• Weight 57 Kg, height 154 cm

• Stopped SGLT2i • Started basal insulin 8 units bedtime deglutec • Follow-up May 2017:

– SMBG (80-180) – HbA1C 9.3 % – Trial of metformin 500 bedtime and glulisine with largest

meal

• Follow-up Sep 2017: – SMBG (100-145) in AM and (180-250) before dinner – Sometimes evening glucose reaches 300-350 – HbA1C 8.0 % – Weight is 70 Kg (gained 13 Kg) – Increased metformin to 1000 mg – Next step to add second glulisine dose – Continue gliclazide and saxagliptin

In conclusion

• Insulin is the oldest and basic therapy

• Demonstrated safety in CV disease

• Need to be familiar with its properties, guidelines, and most importantly to get to know the patient and provide necessary technical and educational support in order to benefit from properties and avoid its side-effects (hypoglycemia and weight gain)