Insulin TherapyWhat is New ?

Dr. Mohammad DaoudConsultant Endocrinologist-ABIM Certified

KAMC/ NGHA - Jeddah –Saudi Arabia

Question?

Is Glycemic Control Better

With New Novel Insulins in

comparison to older ones?

Objectives

Introduction

Insulin :Choices and Profiles

Guidelines

Sequential addition/ titration of Insulin

Over time, glycaemic control deteriorates

*Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/L †ADA clinical practice recommendations. UKPDS 34, n=1704UKPDS 34. Lancet 1998:352:854–65; Kahn et al. (ADOPT). N Engl J Med 2006;355:2427–43

6.2% – upper limit of normal range

Conventional*GlibenclamideMetforminInsulin

UKPDSM

edia

n H

bA

1c(%

)

6.0

7.0

8.0

9.0

Years from randomisation

2 4 6 8 100

7.5

8.5

6.5

Recommended treatment

target <7.0%†

ADOPT GlibenclamideMetforminRosiglitazone

8.0

6.0

7.5

7.0

6.5

Time (years)

0 2 3 4 51

ADA-2015

Correlation of A1C with estimated Average Glucose

A1C (%) Mean plasma glucose mg/dl

6 ̴ 1207 ̴ 150 8 ̴ 180 9 ̴ 210

10 ̴ 240 11 ̴ 270 12 ̴ 300

ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S23; Table 8

Glycemic ControlRecommendations

EMPOWER the Patient

Should be able to

Use data

Adjust Therapy

Avoid / Manage hypoglycemia

(E)

ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S21–S22

B DL HS

Ins

ulin

Eff

ec

t

Bolus Insulin

Basal Insulin

Endogenous Insulin

B, breakfast; L, lunch; D, dinner; HS, bedtime.

Adapted from:

1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.

2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.

Normal Insulin Secretion

Time of Administration

Subcutaneous Insulin Administration

Basal Insulin: Pharmacokinetics

Suppress hepatic glucose production

Maintain near normo-glycemia in the fasting state

*

Basal Insulin: Pharmacokinetics

U-500-R 30-45 min 2-4 hrs 8-24

Glargine -300 1-2 hrs ------ 24 hrs

Degludec (IDeg) 30-90 minutes ------ >42 hrs

PEG-Lispro t ½ 2-3 days ------ > 36 hrs

Suppress hepatic glucose production

Maintain near normo-glycemia in the fasting state

The New –OldU-500 regular insulin

-U-500 is a concentrated form of regular insulin

-Can be used to control hyperglycemia in severely insulin resistant patients usually requiring > 200 u daily

-U-500 insulin has been used successfully in patients with

1. Obesity

2. Immune-mediated insulin resistance,

3. Genetic abnormalities of the insulin receptor

U500 R Insulin

Volume(ml of Insulin)

Actual units of U500 Insulin

0.1 ml 50 units

0.11 ml 55 units

0.12 ml 60 units

Toujeo SoloStar:

300 units/mL (1.5 mL)

Cannot be mixed with rapid-acting insulins.

Insulin Degludec (Tresiba)

100 u nits/ml and 200 units/ml

Insulin Degludec (Tresiba)

Long-acting insulin analog indicated to improve glycemic control in adults with type 1 and 2 diabetes mellitus .

Almost human ; B-chainetion of last amino Soluble multi-hexamer …slowly ..to monomers

For most patients, changing the basal insulin to Tresiba can be done unit-to-unit based on the previous basal

insulin dose .

Basal Insulin: Pharmacokinetics

Degludec (Ideg) t ½ 25 hrs Duration >42 hrs (100 or 200 unit/ml)

Insulin Degludec (Ideg):

Give as short as (8–12 h) and as long as (36–40 h) intervals between doses

Suppress hepatic glucose production

Maintain near normo-glycemia in the fasting state

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70013-5/abstract

Degludec OD vs 3TW

PEG: Ploy Ethylene Glycol

PEG-Lispro Vs Glargine

Better HbA1c and FPG reduction

Less Nocturnal Hypoglycemia and Glycemia variability

Less body weight / Weight loss

Higher liver fat content ,TAG and Transaminases levels

PEG: Ploy Ethylene Glycol

IDeg , Detemir

Glargine ,PEG-Lispro

SA- GLA-11-11-04

Less hypoglycemia and less weight gain with once daily Insulin

Glargine versus three times daily premix Lispro 25/75 & 50/50

• The cross-over ,Sixty insulin-naïve patients T2DM receiving at least two OHAs were

randomised to receive either once-daily insulin glargine + OAD, or premixed insulin lispro

25/75 before breakfast and lunch and 50/50 before dinner for 4 months

• Despite being sub-optimally titrated, Insulin Glargine was associated with

fewer hypoglycaemia events and less weight gain, compared with premix

Malone J, et al. Clin Ther 2004;26(12):2034–2044

The cross-over IONW trial was conducted in the USA. Sixty insulin-naïve patients with T2DM receiving at least two OHAs were randomised to receive either

once-daily insulin glargine, or premixed insulin lispro 25/75 before breakfast and lunch and 50/50 before dinner, for 4 months. Patients continued to receive

their existing OHAs

TID

Nutritional Insulin:

Meal related=Prandial

Control postprandial hyperglycemia

Inhaled Insulin Rapid absorption / elimination

(Afrezza)

Less Hypoglycemia

Better matches

Fast onset and Short duration

RAARAA RAA

RAA=

RAA RAA RAA

RAA=

Inhaled insulinAfrezza

• Afrezza (insulin human) inhalation powder is a rapid-acting Techno-sphere insulin (TI) administered via a breath-powered oral inhaler to patients with diabetes requiring prandial insulin.

• Pre-meal time insulin for Type 1 and 2 diabetics.

• Type 1 diabetics must use in combination with long-acting agent.

• FDA approved June 2014.

AfrezzaLimitations

•Contraindicated In patients who have chronic lung disease .

•Smoker / Stopped less than 6 months ? Not recommended

•Caution in patients at risk for lung cancer

•PFT /Spirometry : Needed for all at baseline, after the first 6 months of therapy and yearly thereafter even in absence of pulmonary symptoms.

Afrezza DOSE

• Insulin-naive patients: ( 4 units at each meal)

• Patients previously on SubQ mealtime (prandial) insulin

Novo-Mix -30/70:

Aspart /Aspart protamine

Ryzodeg 70/30 ;Degludec /Aspart

Humilin 70/30 or Mixtard

70% NPH , 30 % RI

Lispro-Mix 25/75 , 50/50

Lispro /Lispro protamine

Basal Insulin+ GLP-1 RA:

Ideg-Lira

Lixi-Lan

Mixed Insulin

Mixed Insulin - ADA Guidelines

Not recommended for Type 1 DM patients

Type 2 DM patient: If well controlled …continue

Don’t mix Glargine / Detemir with other insulin : Different

PH

NPH + RI mixing …Use immediately

RAI (ex: Lispro / Aspart / Glulisine) + NPH ….

use within 15 minutes

Post-prandial hyperglycaemia

Post-prandial hyperglycaemia

contributes HbA1c ~1%

B=breakfast; L=lunch; D=dinner.

Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.

Pla

sm

a g

luc

ose (

mg

/dL

)

300

200

100

0

Time of day (h)

6 12 18 24 6

Uncontrolled Diabetes HbA1c 8.5%

B

L

D

NormalHbA1c ~5%

Basal Hyperglycaemia Contributes More to Increased HbA1c Levels Than Does Post-prandial Hyperglycaemia

Basal hyperglycaemia

contributes ~2%

Fasting

hyperglycaemia

SA- GLA-11-11-04

62

In T2DM ‘Fix fasting first’ –will lower the entire plasma

glucose through 24 hr

Adapted from Polonsky K. N Engl J Med 1988;318:1231–9 and Hirsch I, et al. Clin Diabetes 2005;23:78–86.

Theoretical simulation of diurnal blood glucose profile

Time of day (hours)

400

300

200

100

006:00 06:0010:00 14:00 18:00 22:00 02:00

Pla

sma g

lucose

(m

g/dL)

Normal

Meal Meal Meal

20

15

10

5

0

Pla

sma g

lucose

(mm

ol/

L)

Hyperglycaemia due to an increase in fasting glucose

T2DM

ADA 2015

SA- GLA-11-11-04

65

When basal insulin is not enough

• Step 1: Think first of titrating the basal insulin dose till

reaching FBG target (Often under-dosage)

• Step 2: Shift to Basal Plus or Basal-bolus (MDI) regimen :

• Number of daily injections up to 4 (1+3)

• Inconvenience

• Risk of hypoglycemia & Weight gain

Add prandial insulin dose (s) as per guidelines

Sequential addition /Titration

Basal +

ADA 2015

Mixed Insulins

ADA 2015

Ryzodeg 70/30Degludec/Aspart

• It is available as a solution for injection in a cartridge (100 units/ml) and in a prefilled pen (100 units/ml)

• It is not known if RYZODEG 70/30 is safe and effective in children under 18 years of age.

Ryzodeg 70/30Degludec/Aspart

• Can be used once or twice daily with any main meal(s)

• Administer a rapid- or a short-acting insulin at other meals if needed.

• Adjust the RYZODEG 70/30 dose according to blood glucose measurements before breakfast (fasting).

• The recommended time between dose increases is 3 to 4 days.

Shifting to Ryzodeg From Once /Twice Daily Basal Insulin alone

Or MDI Regimen From Once Or Twice Daily Premix Or Self-mix Insulin Alone

Start RYZODEG 70/30 at the same unit dose and injection schedule.

Monitor blood glucose after starting therapy due to the rapid-acting insulin component.

Continue the short- or rapid-acting insulin at the same dose for meals NOT covered by RYZODEG 70/30; ex Type 1DM

If a dose of RYZODEG is missed, take the next dose as scheduled on that day ;then resume the usual dosing schedule.

Patients should not take an extra dose to make up for a missed dose

To Conclude…

Summary (continue)

Basal Insulin alone …Break the Ice

0.1-0.3 u /kg or fixed 10 u and adjust

Early on , Don’t switch ….Add(esp. insulin secretagogues; SU /Glinides)

Metformin: Keep unless CI ( Lower insulin doses and less weight gain)

TZDs …decrease or stop (Less risk of fluid retention /heart failure)

Summary (continue)

Basal –Bolus Insulin

TDD = 0.3-0.5 u /kg

Basal Insulin 40-50 %

Meal related :50-60 %

Insulin secretagogues (SU /Glinides): No need

Keep Metformin / maybe TZDs

Summary (continue)

Premixed / Bi-Phasic

TDD = 0.3-0.5 u /kg

2/3 am and 1/3 pm OR

2-3 doses (premixed analogues)

10% adjustment role

Drawbacks:

Hypo /Weight gain/ Larger doses

Insulin secretagogues (SU /Glinides): No need

Keep Metformin / maybe TZDs

Start Low …and Go Slow …

monitor and adjust

Based on a “Trend”

Stepwise (sequential) initiation and titration =

low rate of severe hypoglycemia

Stepwise (sequential) addition of prandial insulin

(start with the main meal) to basal insulin is recommended by

both AACE/Ace and ADA/EASD

Basal + vs MDI

Avoid hypoglycemia

Patient teaching …Core part of the team