INSULIN THERAPY IN TYPE 2 DIABETES

Dharma Lindarto.Div. Endokrinologi-Metabolik Bgn Penyakit Dalam FK USU/RSUP

HAM Medan

Secondary Failure

24-hr insulin profiles in normal, IGT & late Type 2 diabetic subjects

160

140

120

100

80

60

40

20

0Normal

IGT

Insu

lin

(U

/mL

)

0800 1200 1600 2000 2400 0400

Clock time (hours)

Polonsky KS et al. Horm Res 1998; 49: 178–84.

Type 2 diabetesType 2 diabetes

Early Type 2Early Type 2

Insulin Therapy in Type 2

Diabetes Most patients with type 2 diabetes will eventually

need insulin.

As insulin deficiency progresses, a more physiologic multi-component insulin regimen will be required to adequately replace normal insulin secretion.

- Basal insulin

- Meal-Related (prandial, bolus) insulin

Indications for Insulin Therapy in Type 2 Diabetes

Severe hyperglycemia at glucose toxicity To meet glycemic goals Hyperglycemia despite maximum doses of

oral agents Most patients with type 2 diabetes will

eventually need insulin

Profiles of Human Insulins and Analogs

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

Plas

ma

insu

lin

leve

ls

Regular (6–10 hours)

NPH (12–20 hours)

Ultralente (18–24 hours)

Hours

Glargine (20-26 hours)

Aspart, lispro (4–6 hours)

Sources of Insulin for Clinical Use

Human insulin produced by recombinant technology has replaced bovine and porcine insulin preparations

Available as 100 or 500 U/ml labeled U-100 or U-500

Most available without prescription exceptions- U-500, lispro, and glargine

Insulin Preparations

Insulin preparations are formulated to differ in their peaks and durations of action on the basis of factors which alter this rate of dissociation

Insulin associates as hexamers in solution The rate-limiting step for capillary absorption is the

subcutaneous dissociation into dimers and then monomers

Bolus Insulin

(Mealtime or Prandial)

• Limits hyperglycemia after meals• Immediate rise and sharp peak at 1 hour• 10-20% of total daily insulin requirement at each meal

Basal Insulin

• Suppress glucose production

between meals and overnight

• Varying temporal levels based

upon individual physiology

• 50% of daily insulin needs

Protocol for adding insulin to oral agent therapy

Continue oral agent but reduce SU to 50% maximum dose if using NPH at bedtime or

premixed insulin at dinner, or to 25% if using glargine at bedtime

Begin with single dose of 10 U in the evening (or may go to 0,15 U / kg) : NPH at bedtime Glargine at bedtime 70 / 30, 30 min before dinner

Humalog mix 75 / 25 not more than 10 min before dinner

Measure the morning (fasting) BG daily Increase the insulin weekly by : 2 U if FBG is > 120 mg / dl 4 U if FBG is > 160 mg / dl

The goal is to have the morning glucose 90 – 130 mg / dl > 50% of the time if possible with no symptomatic hypoglycemia

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

sma

glu

cose

(m

g/d

L)

300

200

100

0

Time of day (h)6 12 18 24 6

Uncontrolled Diabetes HbA1c 8%

Fasting hyperglycaemia

Basal hyperglycaemia contributes ~2%

B

L

D

NormalHbA1c ~5%

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

Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (P<0.001).Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

Time of day (h)

400

300

200

100

06 610 14 18 22 2

Pla

sma

glu

cose

(m

g/d

L)

Diabetic (untreated)

Normal

Meal Meal Meal20

15

10

5

0

Plasm

a glu

cose (m

mo

l/L)

Treating Basal Hyperglycaemia Lowers the Entire 24-Hour Plasma Glucose Curve

Diabetic (after treatment)

Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

200

100

Time of day (h)

400

300

06 610 14 18 22 2

Normal

Meal Meal Meal

Pla

sma

glu

cose

(m

g/d

L) 20

15

10

5

0

Treating Basal Hyperglycaemia Lowers the Entire 24-Hour Plasma Glucose Curve

Plasm

a glu

cose (m

mo

l/L)

Diabetic(after treatment)

Insulin Preparations

Ultrafast/ultra short-acting: insulin lispro lysine [B28], proline [B29]

LYSPROLYS

PRO

Insulinlispro

Ultrafast/ultra short-acting insulin Insulin lispro

monomeric not antigenic the most rapidly acting insulin used within 15 minutes of beginning a meal short duration of action- must be used with

longer-acting preparation for Type 1 diabetes unless used for continuous infusion

Short-acting insulin

Regular insulin (insulin injection) denoted on vial by “R” zinc insulin crystals in a neutral, nonbuffered,

suspending solution can be given I.V.

Intermediate-acting insulin NPH insulin (Neutral protamine Hagedorn,

isophane insulin suspension) denoted on vial by “N” stoichiometric mixture of regular and protamine

zinc insulin (complexed with excess of positively charged fish sperm protamine)

LENTE insulin (insulin zinc suspension) denoted on vial by “L”30% SEMILENTE insulin (amorphous precipitate

of insulin with zinc in acetate buffer)70% ULTRALENTE insulin

Long-acting insulin ULTRALENTE insulin (extended insulin zinc

suspension) denoted on vial by “U”delayed onset prolonged actionacetate bufferexcess zinc large crystals with low solubility

Ultra long-acting insulin Insulin glargine

Recombinant insulin analog that precipitates in the neutral environment of subcutaneous tissue

Peakless- prolonged action Administered as single bedtime dose

ARG

ARG

ASNGLYInsulinglargine

breakfast

4 8 12 4 8 12 4 8 12

am pm am

breakfast

lunchsnack

dinner

Insulin treatment regimens Conventional insulin treatment

1 or 2 daily subcutaneous injections mixture of short- and intermediate or long-acting

insulins

regular

lente

totaltotal

Other Factors Affecting Insulin Pharmacokinetics

Method of injection Standard- subcutaneous Intradermal- poor absorption Intramuscular - accelerated absorption

Rate of blood flow through injection site Site of injection

absorption from abdomen or buttock faster than from thigh or deltoid

Ambient temperature Exercise

Guidelines for Starting Insulin

Maximum tolerated dose of Oral Hypoglycaemic Agents (OHA)

Failure to reach glycaemic targets (6/12)

Remediable factors considered (e.g. food and exercise plan, intercurrent problems)

Insulin therapy is indicated if the following measures fail to achieve glycaemic targets:

Targets for glycaemic control in Type 2 diabetes

Fasting/preprandial BG* < 6.0 mmol/L Postprandial BG* < 7.7 mmol/L HbA1c < 7.0 %

* Self-monitored blood glucose

A Desktop Guide to Type 2 Diabetes Mellitus, European Diabetes Policy Group 1999

How to START insulin therapy

If more than 30-36 IU of insulin necessary to obtain good metabolic control, consider stopping insulin secretagogues and continue on same total dose of insulin + metformin or actos

Divide the dose into 2 daily injections:2/3 before breakfast1/3 at bedtime

Start insulin twice a day

Replacement Therapy- Twice Daily Insulin

2/3 Daily dose given in the morning

1/3 Daily dose given in the evening

Continuous IV Insulin

In Hospital Setting

Why ?

Randomized prospectively design trialsRetrospective analysis of datae

→→ Support the use of IV insulin infusion→→ Reduced morbidity & mortality, length

of stay, cost

INDICATION Diabetic ketoacidosis Nonketotic hyperosmolar state Critical care illness Myocardial infarction and Cardiogenic shock Postoperative period (Cardiac surgery) Type 1 DM (fasting) General perioperative care (organ

transplantation)

Indication ( cont’d)

Total Parenteral Nutrition Hyperglycemia due to high dose corticosteroid

therapy Failure of SC insulin

When to Start ?

Perioperative Care > 140 mg/dl Surgical ICU Care > 110-140 mg/dl Non Surgical illness > 140-180 mg/dl Pregnancy > 100 mg/dl

Glucose Target Range Critically ill surgical pts : 80-110 mg/dl

Other surgical + non surgical pts : 90 – 140 mg/dl

Woman during labor and delivery : 70 – 100 mg/dl

Protocol should be

Effective with minimal risk of hypoglycemia

Easily used in all hospital units Easily implemented Cost effective

How To Mixing Regular Insulin with 0,9% NS in 1

: 1 or 1 : 2 ratio (250 U / 250 ml or 125 U / 250 ml)

Peggybacked into IV fluid line, 40 ml/hr Pump ~ 0,1 U / hr Bedside monitoring (one hourly until

stable, then two hourly)

Protocol of Van den Berghe

TEST BG RESULT ACTION

BG ON ENTRY TO ICU > 220 mg/ dl START INSULIN 2 - 4 U / h 110 – 220 mg / dl START INSULIN 1 – 2 U / h < 110 mg / dl DO NOT START INSULIN, CONTINUE BG MONITORING EVERY 4 h

MEASURE BG EVERY 1 – 2h > 140 mg / dl ↑ INSULIN DOSE BY 1 – 2 U / h→ WITHIN NORMAL RANGE 110 – 140 mg / dl ↑ INSULIN DOSE BY 0,5 – 1 U / h APPROACHING NORMAL RANGE ADJUST INSULIN DOSE BY 0,5 – 1 U / h

TEST BG RESULT ACTION

MEASURE GLUCOSE EVE- APPROACHING NOR- ADJUST INSULIN DOSE BYRY 4 h MAL RANGE 0,5 – 1 U / h

N O R M A L INSULIN DOSE UNCHANGED

DECLINING STEEPLY ↓ INSULIN DOSE BY HALF CHECK BG MORE FREQ. 60 – 80 mg / dl ↓ INSULIN DOSE, CHECK BG WITHIN 1 h 40 – 60 mg / dl STOP INSULIN, ENSURE ADEQUATE GLUC INTAKE, CHECK BG WITHIN 1 h < 40 mg / dl STOP INSULIN, ENSURE ADEQUATE GLUC INTAKE, ADM 10 G GLUCOSE IV CHECK BG WITHIN 1 h

Risk Hypoglycemia : < 40 mg/dl (2,6%-5,2%) Correction : (100 – current BG) X 0,4 = …… ml D50 (D50 = 1,25 D40) → X 0,5Target : 100 mg/dl Every 25 g Glucose, ↑ BG 125 mg/dl

Conversion from IV to SC Condition : volume resuscitation/

pressor support has been discontinued, resume eating, stable BG in target range (6 – 8 hrs)

Consist of : Basal SC insulin Nutritional SC insulin Correction SC insulin

IV insulin continue 2 hrs ( to avoid ketoacidosis)

SC total daily dose (TDD) = 80% total daily iv insulin dose

Basal dose = 50% TDD Bolus dose (nutritional) = part of 50% TDD Correction dose = (current BG – target BG)

: CF (correction factor) CF = 1700 : TDD

Transition from IV to SC insulin

Average 2 U / h IV during previous 6 h. Recommended doses are as follows : SC TDD = 80% of 24 h insulin requirement : 80% of ( 2 U x 24 = 48 U ) → 38 U Basal dose is 50% of SC TDD : 50% of 38 U → 19 U of long acting analogue Bolus total dose is 50% of SC TDD : 50% of 38 U → 19 U of total prandial rapid

acting analogue or ~ 6 U with each mealCorrection dose is actual BG minus target BG, divided by correction factor (CF) CF is equal to 1700 divided by TDD : CF = 1700 : 38 → ~ 40 mg/dl Correction dose = ( BG – 100 ) : 40

Future directions in insulin therapy Inhalable insulin- Phase III

use for postprandial glucose load in combination with ultralente or glargine for basal insulin

Oral insulin- modified with amphiphilic polymers to prevent enzymatic digestion and facilitate uptake; Phase II use in combination with ultralente or glargine as above

Gene therapy glucose responsive promoters glucose responsive cell types

Artificial pancreas: sensor, pump, control system

Summary Early and aggressive treatment of Type 2 diabetes to

improve glycaemic control decreases the risk of long-term complications

Type 2 diabetes is a progressive disease: progressive loss of beta cell function is observed during the natural course of the disease

Insulin treatment should be initiated when near normalization of blood glucose cannot be achieved with OHAs

Continuous IV Insulin,Reduced morbidity & mortality, length of stay, cost