Document

Report
Insulin therapy
in Type 2
Diabetes:
Current and
Future
Directions
When we started insulin?
1.
2.
Type 1
Sometimes Type 2
Pharmacologic Therapy
for Type 2 Diabetes






Sulfonylureas (glyburide, glipizide,
glimepiride)
Biguanides (metformin)
Alpha-glucosidase inhibitors (acarbose,
miglitol, voglibose)
Benzoic acid analogues (repaglinide)
Thiazolidinediones (troglitazone,
rosiglitazone, pioglitazone)
Insulin (human insulin, insulin analogues)
Treatment Algorithm
Nonpharmacologic therapy
Monotherapy
Sulfonylureas/Benzoic
acid analogue
Biguanide
Alpha-glucosidase
inhibitors
Thiazolidinediones
Insulin
Combination therapy
Very symptomatic
Severe hyperglycemia
Ketosis
Latent autoimmune
diabetes
Pregnancy
Insulin

All patients with type 1 diabetes need insulin
treatment permanently, unless they receive an
islet or whole organ pancreas transplant; many
patients with type 2 diabetes will require insulin
as their beta cell function declines over time.
Indications for insulin therapy




unexplained recent weight loss (irrespective of
the initial weight),
a short history with severe symptoms,
the presence of moderate to heavy ketonuria.
pregnancy
Type 2 DM
A.
B.
C.
D.
E.
F.
G.
H.
I.
J.
Patient with persistent elevated FPG leves (200- 300mg/dl) or
ketonuria or ketonemia
FPG more than 300 mg/dl with polyuria, polydipsia and weight
loss
Gestational diabetes
Uncontrolled diabetes with oral agents
Physician-patient option wish to receive insulin as initial therapy
Wasting state
Latent autoimmune diabetes in adult
Post MI
Renal failure
Allergy or serious reaction to oral agents
Types of insulin
Types of insulin




Insulin glargine :
No real advantage with regard to A1C
Lower fasting blood glucose and fewer
hypoglycemic episodes
Do not mix with other insulin
Glargine:
A New Long-Acting Insulin
Analogue

Modifications to human insulin chain
Substitution of glycine at position A21
 Addition of two arginines at position B30
 Unique release pattern from injection site

Gly
1
5
10
15
20 Asn
1
5
10
15
20
Substitution
25
30
Extension
Arg Arg
Characteristics of Insulin
Glargine

Euglycemic clamp studies vs. NPH
Smooth continuous release from injection site
 Longer duration of action
 Continued effect at end of 24-hour clamp
study



No differences in the absorption rate from
arm, leg, or abdominal sites
No inflammatory reactions at any of the
injection sites
Insulin detemir


Its duration of action appears to be substantially
shorter than that of insulin glargine,
Compare to NPH insulin detemir may be
associated with slightly less nocturnal
hypoglycemia and weight gain
Very-rapid-acting insulin



lispro,
aspart
glulisine
Onset of action within 5
to15 Peak action at 30 to 90
Duration of action of two to
four hours.
Clinical Efficacy of Insulin
Lispro

Worldwide clinical trials of insulin lispro in
>10,000 patients with type 1 or type 2 diabetes

Dosage regimen: insulin lispro 10 min
before and soluble human insulin 30 to 45
minutes before meals, with NPH or
ultralente insulin as the basal insulin
supplement
Advantages of very rapid acting to regular





decreases the postprandial rise in blood glucose
reduce the frequency of hypoglycemia
It is more convenient because it can be injected
immediately before meals
No difference in A1C
Need to increase in the dose of NPH when a
patient is switched from regular insulin to a
very-rapid-acting insulin

The teratogenicity and long term safety profile
of rapid-acting insulins in pregnancy are
unknown, although many diabetologists do
prescribe very-rapid-acting insulins during
pregnancy.
CHOICE OF INSULIN REGIMEN



The basic requirements are :
Baseline dose of insulin (whether an
intermediate or long-acting insulin or given via
CSII) plus
Adjustable doses of pre-meal rapid-acting
insulin (regular) or very-rapid-acting insulin
analogs (lispro, aspart, or glulisine).
Method of Insulin Preparation


Conventional insulin therapy
Intensive insulin therapy:
MSI
CSII
Getting started




Start on a total daily dose of 0.2 to 0.4 units of
insulin per kg per day, although most will
ultimately require 0.6 to 0.7 units per kg per day.
One-half of the total dose as a basal insulin
(2/3 in the morning 1/3 in the bed time
The remainder is given as rapid or very rapidacting insulin, divided before meals.
The pre-meal dosing is determined by the usual
meal size and content, as well as activity and
exercise pattern.
Conventional insulin therapy
Methods of MSI
Major drawback to intensive therapy



Cost (three times )
Weight gain
Risk of hypoglycemia (three times)
When to start intensive therapy

Intensive therapy should be started as early as
possible following the diagnosis of type 1
diabetes.

Intensive insulin therapy
Residual beta cell function
lower risk of hypoglycemia
MANAGEMENT ISSUES
 Consistency



The content and timing of meals,
The site of insulin injections,
The timing and frequency of exercise.
 SMBG

Four to seven times daily
Insulin Pump
 CSII:
uses portable infusion pump
connected to an indwelling
subcutaneous catheter to deliver
short-acting insulin
MSI or CSII



Same efficacy,
Same frequency of hypoglycemic events,
Same impact on quality of life for most patients
MSI


CSII
For a patient who has been well controlled on
his previous MSI (eg, A1C <7.0 percent), the
initial total daily dose of insulin administered by
pump may be 10 to 20 percent less than the total
daily dose of the previous regimen.
Conversely, patients with inadequate glycemic
control may be started with the same total daily
dose as they had been using with their injection
regimens.


In general, approximately one-half of the total
daily dose is administered as basal rate.
For most patients, basal rates are in the range of
0.01 to 0.015 units per kg per hour (ie, for a 60
kg woman approximately 0.6 to 0.9 units per
hour).
Advantages of CSII instead of MSI




Slightly better glycemic control (lower A1C)
The use of very-rapid-acting insulin instead of
regular may result in a lower A1C, less
hypoglycemia, and less weight gain
More flexibility in the timing of meals
Insulin absorption is less variable from day to
day
Disadvantages of CSII instead of
MSI




Cost
Infection at the site of needle insertion
infusion-system failure
DKA is more common
Insulin Pump
Insulin therapy
in Type 2
Diabetes:
Current and
Future
Directions
Pharmacologic Therapy
for Type 2 Diabetes






Sulfonylureas (glyburide, glipizide,
glimepiride)
Biguanides (metformin)
Alpha-glucosidase inhibitors (acarbose,
miglitol, voglibose)
Benzoic acid analogues (repaglinide)
Thiazolidinediones (troglitazone,
rosiglitazone, pioglitazone)
Insulin (human insulin, insulin analogues)
Treatment Algorithm
Nonpharmacologic therapy
Monotherapy
Sulfonylureas/Benzoic
acid analogue
Biguanide
Alpha-glucosidase
inhibitors
Thiazolidinediones
Insulin
Combination therapy
Very symptomatic
Severe hyperglycemia
Ketosis
Latent autoimmune
diabetes
Pregnancy
Insulin
FPG (mmol/L) or HbA 1c (%)
UKPDS: Effect of Intensive
Therapy on Glycemia
FPG, Conventional (N=1138)
FPG, Sulfonylurea (N=1573) or Insulin (N=1156)
HbA1c, Conventional
HbA1c, Sulfonylurea or Insulin
10
9
8
7
6
0
1
3
Years
UKPDS Group. Lancet. 1998;352:837-853.
5
7
9
UKPDS 10-Year Cohort Data:
Reductions With Intensive vs.
Conventional Therapy
0
-6%
-10
-11%
-10%
-12%
(P= 0.029)
-16%
(P= 0.052)
-20
-25%
(P= 0.0099)
-30
HbA1c
All-Cause Mortality Diabetes-Related
Death
UKPDS Group. Lancet. 1998;352:837-853.
Any DiabetesRelated
Complication
Myocardial
Infarction
Microvascular
Complication
Summary of Key Findings

Kumamoto trial:
Intensive insulin treatment reduced
microvascular complications
 Established glycemic threshold to prevent onset
and progression of complications


UKPDS:
Diet therapy alone inadequate in two thirds of
patients
 Pharmacologic therapy plus nutrition/exercise
necessary
 Weigh benefit:risk ratio
 No threshold for HbA1c reduction in reducing
complications
 Insulin does not increase macrovascular disease

Strategies for Insulin Therapy in
Elderly Patients


Insulin therapy often considered a last
resort in the elderly
Therapeutic goals:
Relieve symptoms
 Prevent hypoglycemia
 Prevent acute complications of hyperglycemia


Ways to facilitate insulin treatment:
Simple dose schedules
 Premixed preparations
 Improved, more convenient delivery systems

Combination Therapy:
Oral Agents Plus Insulin

Rationale



Sulfonylurea + Insulin



BIDS therapy: bedtime insulin/daytime sulfonylurea
Useful in patients early in course of disease
Metformin + Insulin


Combination of two agents with different
mechanisms of action
More convenient and may be safer
Improves insulin sensitivity
Alpha glucosidase inhibitor (acarbose) +
Insulin
Change From Baseline Values
Meta-Analysis of
Sulfonylurea/Insulin
Combination Therapy
2
Sulfonylurea + Insulin
Insulin Only
1.4
0.8
1
0
-1
-0.25
-0.6
-1.1*
-2
-3
-2.5*
Fasting Serum Glucose
(mg/dL)
HbA1c (%)
* P< 0.05 vs. baseline value
Johnson JL, et al. Arch Intern Med. 1996;156:259-264.
Weight (kg)
Comparison of Insulin
Regimens
Among Oral Treatment Failures
10
8
Morning NPH (N= 32)
Evening NPH (N= 28)
Twice-daily injections (N= 29)
Multiple-daily injections (N= 30)
Control (N= 30)
6
4
2.2*
2
2.9*
1.2* †
1.8*
0
-2
-0.5
-1.7*
-1.9*
-1.8*
-0.9
-1.6*
-4
Change in HbA1c (%)
Weight Change (kg)
* P< 0.001 vs. control group
†P< 0.05 vs. other insulin treatment groups
Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.
Need for Novel Delivery

Disadvantages
conventional
Systems
of ofInsulin
subcutaneous injection:
Discomfort
 Inconvenience
 Systemic delivery
 Inconsistent pharmacokinetics
 Irreversible after injection




Insulin pumps: too complex, limited
experience and utility with type 2
Insulin pen: beneficial but underutilized
Systems in clinical testing

Inhaled formulation
Insulin Pen

Benefits
More accurate dosing mechanisms
 Faster and easier than conventional syringes
 Improved patient attitude and compliance


Advantages of newer insulin pens
LCD display to show dosage setting
 Dosage settings change quickly and easily
 Safety button automatically resets after drug delivery

Insulin Pen
Inhaled Insulin Formulations
% Change From Baseline
Changes in Glycemic Parameters
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
-50
Inhaled human insulin
Subcutaneously injected
insulin
HbA1c
2-hr PG
Gelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.
Continuous Glucose Sensors




When available, may provide only mechanical
means of achieving “normal” glucose
homeostasis
Will direct insulin delivery automatically on
demand (“closed loop”)
One technology uses reverse iontophoresis to
noninvasively extract and measure glucose levels
Technical challenge to develop
Conclusions




Type 2 diabetes: gradual deterioration of glycemic
control
Significant morbidity and mortality; tight glycemic
control reduces risk of complications
Earlier institution of insulin may help attain initial
glycemic control
Objectives of insulin therapy:




Achieve normal fasting glucose levels
Achieve normal postprandial glucose levels
Minimize hypoglycemia
Intensive insulin therapy should:
Conclusions (cont’d)

New delivery systems:
Reduce limitations of conventional insulin syringes
 Improve patient compliance and disease
management


New long-acting insulin analogues (eg, insulin
glargine):
Produce flat insulin profile with no peaks
 Allow once-daily administration
 Significantly reduce nocturnal hypoglycemia

Type of insulin available
1.
2.
3.
4.
5.
Regular insulin
Insulin analogues, Lispro, Glargine
Alternate delivery system pump , pulmonary,
intranasal , ocular, rectal , transdermal
Combination with oral agents
Initiating insulin in patient on oral agents
bedtime insulin
What regimens are best for type 1?

Newly diagnosed patients or latent autoimmune
DM may do well receiving once or twice basal
insulin

Physiological regimens or both prandial and
basal insulin is required in severe insulin
deficiency
Practical strategy to start insulin in
type 2 DM

Continue oral agents at the same dose
(eventually reduce)

Add single evening dose(5 -10 IU) for thin and
(10-15 IU) for obese patients

Adjust dose weekly 2-4 IU
How dose the patient use
supplement and adjustment ?

A conservative dose for type 1 is additional 1 IU per 50
mg /dl above the target

For type 2 DM 1IU per 30 mg/dl above the target

If patients are to inject supplements less than 3 hours
after previous insulin they can decrease it 50%
Meal bolus insulin
Exercise
* The dose should be decrease by 30% for
postprandial exercise of less than one hour, 40
% for 1-2 hours, 50 % for more than two hours
Food
* Insulin requirement approximately 1 unit of
insulin per 15 g carbohydrate
Experience


Each patient must educated for insulin and
blood glucose and record data
Blood glucose and insulin logs should be
reviewed weekly until goal
Discontinuation of insulin in T2DM




Reduce the dose by 10 to 15% of total dose
If the blood glucose rise, restore the initial dose
If the blood glucose dose not rise reduce 10 %15% every 1-2 weeks
When daily dose reached to 0.2- 0.4 u/kg
consider discontinuing insulin
Benefits of combination therapy?








Reduces fasting and postprandial glucose
Directly suppresses hepatic glucose production
Reduce free fatty acid levels
Counteracts dawn phenomenon
Minimal education needed
Easily started on an outpatient state
Better compliance
Less total exogenous insulin needed

similar documents