Upload
yanti-moon
View
41
Download
7
Embed Size (px)
Citation preview
INSULIN THERAPY IN TYPE 2 DIABETES
Dharma Lindarto.Div. Endokrinologi-Metabolik Bgn Penyakit Dalam FK USU/RSUP
HAM Medan
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
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
Replacement Therapy- Twice Daily Insulin
2/3 Daily dose given in the morning
1/3 Daily dose given in the evening
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