PRACTICAL GUIDE TO INSULIN THERAPY

Jeyakantha RatnasingamJuly 2011

Toronto , 1921

Jan 11 , 1922

History & background

Diabetes mellitus discovered more than 3000 years ago

Known as melting down of flesh and limbs into urine

Until early 1920 , treated with diet restriction of calories

Discovery of insulin revolutionised treatment

Worldwide out of 117 million diabetics , 50 million are on insulin

Insulin structure

Insulin structure

Since discovery , bovine ( differs in 3 AA ) & porcine insulin was used ( differs in 1 AA )

1978 , recombinant human insulin produced , Humulin , by injecting gene for human insulin into bacteria

1996 , insulin receptor ligands or analogues were produced ( Lispro )

Lecture Outline

Types of insulin Pharmacokinetics Insulin Regimens How & when to start Intensification Monitoring Practical issues

Introduction

Used in all T1DM Adjunctive therapy with insulin in type

2 diabetes is both safe and effective Choice of insulin and/or regimen is

dependent upon: The patient Pre-existing glycemic control Duration of illness

Insulin in T2DM

• Type 2 DM results from insufficient insulin secretion due to beta celldysfunction• Over time beta cell function continues to deteriorate resulting inincreasing blood glucose levels• Elevated glucose levels can lead to diabetes complications, progressionof disease and deteriorating health• Treatment of elevated blood sugars slows the gradual worsening ofhealth• Insulin injections will eventually be required to replace the body’sown insulin, control blood sugar and slow disease progression

(derived from Practical Guidance to Insulin Management – Primary Care Diabetes4 Supplement 1 ( 2010) S43 – 56)

Short term use of insulin therapy in patients with T2DM may also be considered in

• Acute illness, surgery, stress and emergencies

• Pregnancy • Breast-feeding • As initial therapy in T2DM with

marked hyperglycemia • Severe metabolic decompensation

(eg. DKA, HHS

TYPES OF INSULIN & PHARMACOKINETICS

Insulin preparations

-Prandial insulin covers prandial glucose excursion.

- Basal insulin covers the basal insulin requirements inbetween meals and overnight due to endogenous hepatic glucose production.

-Premixed insulin is biphasic insulin that incorporates the combination of short or rapid-acting insulin with its intermediate-

acting counterpart to cover for both postprandial glucose excursion as well as basal insulin needs simultaneously

Insulin Analogues

Insulin analogue is derived from human insulin in which the amino acid sequence is intentionally altered to produce an improved pharmacokinetic profile that mimics physiological insulin secretion better.

When to consider analoguesRapid Acting Analogues

Long Acting Analogue

- Delayed inter-meal hypoglycemia preventing achievement of postprandial glycemic target on regular short-acting insulin

- Lifestyle restriction, the need to eat immediately after insulin injection due to job schedule etc.

- Variable carbohydrate intake

- Nocturnal hypoglycemia on intermediate-acting insulin (NPH) preventing achievement of target fasting blood glucose

- Inadequate basal insulin coverage with once daily intermediate-acting insulin

(NPH) and not willing to go on NPH twice daily

Newer Insulins

MODIFCATION

ONSET (hr)

PEAK (hr)

DURATION (hr)

LISPRO (Humalog)

b-chain Pro®Lys28 b-chain Lys®Pro29

0.25-0.5 1-2 3-5

ASPART (NovoLog)

b-chain Pro®Asp28

0.25-0.5 1-2 2-4

GLULISINE (Apidra)

b-chain Lys®Asn3 b-chain Lys®Glu29

Similar Similar Similar

GLARGINE (Lantus)

b-chain Asp®Gly21 b-chain Arg31/Arg32

1 None 24

DETEMIR (Levemir)

b-chain Lys29(Ne-tetradecanoyl)des(b-thr30)

2 6-8 18

NPH Native insulin complexed with protamine

1-4 8-10 12-20

Lispro Structure

Glulisine Structure

Aspart Structure

Insulin Preparations in Malaysia

Insulin Type Conventional Analogue

Prandial Short-acting regular human insulin- Actrapid®- Humulin R®

Rapid-acting- Novorapid® (Aspart)- Humalog® (Lispro)- Apidra® (Glulisine)

Basal Intermediate-acting or NeutralProtaminated Hagedorn (NPH)Insulin- Insulatard®- Humulin N®

Long-acting- Lantus® (Glargine)- Levemir® (Detemir)

Premixed Combination of short &intermediate-acting:30% regular insulin + 70% NPH- Mixtard® 30- Humulin® 30/70

Combination of rapid-acting &protaminated analogue- NovoMix® 30 (30% aspart+ 70% aspart protamine)- Humalog Mix® 25 (25% lispro+ 75% lispro protamine)

Why analogues are different ?

Look at mechanism of diffusion of insulin

Insulin Diffusion

Pharmacokinetic profiles of various insulin

Type Onset Peak (hr) Duration (hr) Insulin timing

a) Short-acting, regular- Actrapid®*- Humulin R®*

30 min30 min

1-32-4

86-8

30 minsbefore meal

b) Rapid-acting analogue- Novorapid® (Aspart)*- Humalog® (Lispro)*- Apidra® (Glulisine)

10-20 min0-15 min5-15 min

1-311-2

3-53.5-4.53-5

5-15 minsbefore orimmediatelyafter meals

c) Intermediate-acting, NPH- Insulatard®*- Humulin N®*

1.5 Hr1 Hr

4-124-10

18-2316-18

Pre-breakfast /Pre-bed

d) Long-acting analogue- Glargine®*- Detemir®*

2-4 Hr1 Hr

peaklesspeakless

20-2417-23

Same timeeveryday atanytime of theday

e) Premixed human (30%regular insulin+ 70% NPH)- Mixtard® 30*-Humulin® 30/70*

30 min30 min

dualdual

18-2316-18

30-60 minsbefore meals

f) Premixed analogue- NovoMix® 30(30% aspart + 70%aspart protamine)*- Humalog Mix® 25(25% lispro + 75%lispro protamine*

10-20 min

0-15 min

dual

dual

18-23

16-18

5-15 minsbefore meals

Analog Insulin Profiles

Rosenstock J. Clin Cornerstone. 2001;4:50-61.

0 2 4 6 8 10 12 14 16 18 20 22 24

Pla

sma In

sulin

Levels

Time (hr)

NPH (10–20 hr)

Regular (6–10 hr)

Glargine (~24 hr)

Aspart, Lispro, Glulisine (4–5 hr)

Detemir ~18hr

Note

General rule for these pharmacokinetics may vary :

between patients during stress and illness At different site administered Different times

INSULIN REGIMENS

Insulin Regimen should

Mimic physiological response to meals & endogenous hepatic glucose production

INDIVIDUALISED based on-glycaemic profile-dietary pattern-lifestyle-desired flexibility-affordability

Insulin regimens & Frequency of injectionsNo of injections Insulin Regime Type of insulin & timing

1 Basal

Basal

Premixed OD

Intermediate acting (NPH) insulin pre-bed

Long-acting analogue once daily

Premixed/ premixed analogue pre-dinner

2 Basal

Premixed BD

Basal Plus ( 1 )

Intermediate acting (NPH) pre-breakfast and pre-dinner

Premixed insulin pre- breakfast and pre-dinner

Basal insulin once daily + 1 prandial insulin

3 Basal Plus ( 2 )

Prandial

Premixed TDS

Premixed Plus

Premixed Plus

Basal insulin once daily + 2 prandial insulin

Prandial insulin pre-breakfast, pre-lunch and pre-dinner

Premixed analogue pre-breakfast, pre-lunch and pre-dinner

Premixed analogue pre-breakfast, pre-dinner + 1 prandial pre-lunch

Prandial insulin pre-breakfast and pre-lunch +premixed insulin pre-dinner

4 Basal Bolus Basal insulin once daily + prandial insulinpre-breakfast, pre-lunch and pre-dinner

5 Basal Bolus Intermediate acting (NPH) insulin pre-breakfastand pre-dinner + prandial insulin pre-breakfast , pre-lunch , pre-dinner

Normal Pancreas

Insulin is released in response to varying blood glucose levels and hypoglycemia does not occur

Insu

lin

Eff

ect

Basal Insulin (~0.5-1.0 U/hr)

‘Bolus’ Insulin (Meal Associated)

B DL HS

Insu

lin E

ffe

ct

Sensitizer Basal InsulinSecretagogue

Basal Insulin Regimen

Insu

lin E

ffe

ct

B DL HS

Bolus insulin

Basal insulin

Basal-Plus Insulin Therapy

Endogenous insulin

Adapted from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193

Basic Insulin Regimen: Split-Mixed Regimen or Premix

Regular

NPH

B DL HS B

Endogenous insulin

Insu

lin E

ffe

ct

B DL HS

Bolus insulin

Basal insulin

Basal-Bolus or Physiologic Insulin Therapy

Endogenous insulin

Adapted from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193

Some 34 years ago, when I was diagnosed with type 1 diabetes, I was treated with different types of insulin that reflect the progressive development in the field:

1. Insulin extracted from pigs. 2. "Human" insulin (Humulin).3. Insulin analog – genetically engineered.

During the last 30 years since the development of the "human" insulin the formula has doubtlessly undergone significant improvement, ameliorating our quality of life. I can only wish that the next stage in insulin development will arrive quickly and produce still greater change.

Imagine how our lives would look like should "smart" insulin be invented – a substance that becomes active only if the blood sugar level rises above a certain mark. How many instances of hypoglycemia we diabetics will be spared from?

Future ?

Oral insulin Inhaled insulin

Elliot Joslin 1923

“Insulin is a remedy primarily for the wise and not the foolish , whether they be patients or doctors . Everyone knows it requires brains to live long with diabetes , but to use insulin successfully requires more than brains .”