Jeyakantha Ratnasingam July 2011

PRACTICAL GUIDE TO INSULIN THERAPY

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 cell dysfunction Over time beta cell function continues to deteriorate resulting in increasing blood glucose levels Elevated glucose levels can lead to diabetes complications, progression of disease and deteriorating health Treatment of elevated blood sugars slows the gradual worsening of health Insulin injections will eventually be required to replace the bodys own insulin, control blood sugar and slow disease progression

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 & PHARMACOKINETI CS

Insulin preparations
-Prandial insulin covers prandial glucose excursion.

- Basal insulin covers the basal insulin requirements in between 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

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 analogues

Rapid Acting Analogues - Delayed inter-meal hypoglycemia preventing achievement of postprandial glycemic target on regular shortacting insulin - Lifestyle restriction, the need to eat immediately after insulin injection due to job schedule etc. - Variable carbohydrate intake

Long Acting Analogue

- Nocturnal hypoglycemia on intermediate-acting insulin (NPH) preventing achievement of target fasting blood glucose - Inadequate basal insulin coverage with once daily intermediateacting insulin (NPH) and not willing to go on NPH twice daily

Newer Insulins
ONSET (hr) 0.25-0.5 0.25-0.5 PEAK (hr) 1-2 1-2 DURATION (hr) 3-5 2-4 Similar 24 18 12-20

MODIFCATION LISPRO (Humalog) ASPART (NovoLog) GLULISINE (Apidra) GLARGINE (Lantus) chain Pro 28 Lys chain Lys 29 Pro chain Pro Asp28 chain Lys Asn 3 chain Lys Glu 29 chain Asp 21 Gly 31 chain Arg /Arg32

Similar Similar 1 2 None

29 DETEMIR chain Lys (N ( Levemir) tetradecanoyl)des(thr30 ) -

6- 8
8-10

NPH

Native insulin complexed 1-4 with protamine

Lispro Structure

Glulisine Structure

Aspart Structure

Insulin Preparations in Malaysia

Insulin Type Prandial Basal Premixed Conventional Short-acting regular human insulin Intermediate-acting or - Actrapid Neutral R - Humulin Combination of short & Protaminated Hagedorn intermediate-acting: (NPH) 30% regular insulin + Insulin 70Insulatard - % NPH - MixtardN Humulin 30 - Humulin 30/70 Analogue Rapid-acting - Novorapid (Aspart) Long-acting(Lispro) - Humalog - Lantus (Glargine) ) Apidra Glulisine Combination(Detemir) - Levemir 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 a ) Short - acting , regular - Actrapid * - Humulin R* b ) Rapid - acting analogue - Novorapid (Aspart)* - Humalog (Lispro)* - Apidra (Glulisine ) Onset Peak (hr) Duration (hr) Insulin timing

30 min 30 min 10-20 min 0-15 min 5-15 min

1-3 2-4 1-3 1 1-2

8 6-8 3-5 3.5-4.5 3-5

30 mins before meal 5-15 mins before or immediately after meals

c ) Intermediate - acting , NPH - Insulatard * 1.5 Hr - Humulin N* 1 Hr d ) Long - acting analogue - Glargine * - Detemir *

4-12 4-10 peakless peakless

18-23 16-18 20-24 17-23

Pre-breakfast / Pre-bed Same time everyday at anytime of the day

2-4 Hr 1 Hr

e ) Premixed human ( 30 % regular insulin + 70 % NPH ) 30 min - Mixtard 30* 30 min Humulin 30/70* f ) Premixed analogue - NovoMix 30 (30% aspart + 70% aspart protamine)* - Humalog Mix 25 (25% lispro + 75% lispro protamine*

dual dual

18-23 16-18

30-60 mins before meals

10-20 min 0-15 min

dual dual

18-23 16-18

5-15 mins before meals

Analog Insulin Profiles

Aspart, Lispro, Glulisine (45 hr) Regular (610 hr)
Plasma Insulin Levels

NPH (1020 hr) Detemir ~18hr

Glargine (~24 hr)

10

12

14

16

18

20

22

24

Time (hr)
Rosenstock J. Clin Cornerstone. 2001;4:50-61.

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 injections

No of injections 1 2 3 4 5 Insulin Regime Basal Basal Basal Premixed OD Basal Plus ( 2 Premixed BD ) Prandial Basal Plus ( 1 ) Basal Bolus Premixed TDS Basal Bolus Premixed Plus Premixed Plus Type of insulin & timing Intermediate acting (NPH) insulin pre-bed Long-acting analogue once daily Intermediate acting (NPH) pre-breakfast and Premixed/ premixed analogue pre-dinner pre-dinner Premixed insulin pre- breakfast and preBasal insulin once daily + 2 prandial dinner insulin Basal insulin once daily + 1 prandial Prandial insulin pre-breakfast, pre-lunch and Basal insulin once daily + prandial insulin insulin pre-dinner pre-breakfast, pre-lunch and pre-dinner Premixed analogue preNPH) insulinpre-lunch Intermediate acting ( -breakfast, preand pre-dinner breakfast and pre-dinner + prandial insulin prePremixed analogue pre-breakfast, pre-dinner + breakfast , pre-lunch , pre-dinner 1 prandial pre-lunch Prandial insulin pre-breakfast and pre-lunch + premixed insulin pre-dinner

Normal Pancreas

Bolus Insulin
Insulin Effect

(Meal Associated)

Basal Insulin

(~0.5-1.0 U/hr)
Insulin is released in response to varying blood glucose levels and hypoglycemia does not occur

Basal Insulin Regimen

Sensitizer Secretagogue Basal Insulin

Insulin Effect

HS

Basal-Plus Insulin Therapy

Endogenous insulin Bolus insulin

Insulin Effect

Basal insulin

HS

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

Basic Insulin Regimen: SplitMixed Regimen or Premix

Endogenous insulin Regular NPH

HS

Basal-Bolus or Physiologic Insulin Therapy

Endogenous insulin Bolus insulin

Insulin Effect

Basal insulin

HS

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 .