Transcript No Slide Title

10th Meeting of the MGSD
26-29 April, 2007
Istanbul, Turkey
THE EXTERNAL PUMP IN
PRACTICE
Predrag B. Djordjevic
Academy, US Medical School, Belgrade,
Serbia
• In 1993, the Diabetes Control and Complications Trial
(DCCT) definitively showed that, in people with type 1
diabetes, a good metabolic control, meaning long-term
glucose values as close to normal as possible, (mean
HbA1c - 7.2 % in the intensive treatment group,
compared to conventional treatment, with a mean
HbA1c - 9.0 %) is associated with a significant
reduction in the risk for retinopathy (76 %),
nephropathy (50%) and neuropathy (60%).
• Further on, the DCCT / EDIC study (Epidemiology of
Diabetes Interventions and Complications) has
demonstrated the sustained benefits of good metabolic
control through intensive insulin therapy: the former
intensive treatment group continues to exhibit the
same reduction in the risks of diabetic retinopathy (75
%), nephropathy (75 %) and neuropathy, starting
from a new baseline status at the beginning of EDIC.
• Also cardiovascular events have been
reduced by 42 % and the major
cardiovascular events (non-fatal MI,
stroke, death), by 57 %.
• The EDIC study has demonstrated the
concept and the importance of the
“metabolic memory” in preventing the
later course of complications.
• The release of DCCT and UKPDS has definitively
demonstrated the importance to optimize
glycemic control, either through multiple daily
injection or continuous subcutaneous insulin
infusion (CSII or insulin pump therapy) and also
has renewed interest in the role of CSII therapy
in improving metabolic outcomes, because it
offers a more precise physiological method of
insulin administration.
•NPH (
)
•Glargine (
)
•Short-acting insulin (
•22.00
•ui
3.00
6.00
)
14.00
18.00
22.00
•Bolus (prandial) insulin
• Figure 3. Basal-bolus insulin regimen
•H
• The use of insulin glargine as basal insulin
therapy has significantly improved the
glycaemic control, with a lower rate of
hypoglycaemia. Its flat profile of action, the
24 hours duration and a more predictable
absorption are important advantages.
However, multiple daily injection treatment
still has some limits
 Insufficient cover of “dawn” phenomenon
• Insufficient cover of “dusk” phenomenon
 Excessive insulin during the night, when the high
insulin sensitivity may predispose to hypoglycaemia
 Delayed action of basal insulin in the morning
 Variable absorption of insulin, ranging from 19%
to 55%, leading to glycaemic fluctuations
• Flexible lifestyle can be maintained under certain
circumstances
• Increased number of injections.
• A quarter of a century after its
introduction, insulin pumps are widely
used in clinical practice, there are now
estimated to be >300,000, with
approximately 250,000 in the U.S.
• For CSII as a form of IIT external insulin pumps are
used. These operate with the help of short acting
(regular) or rapid acting insulin analogues. The insulin
is delivered trough a catheter inserted subcutaneously
(the abdomen is preferred site). Basal Rate (BR) of
insulin infusion (24h) and insulin boluses (BS) are
delivered automatically using the individual programs.
Insulin pump therapy: technical data
 Modern insulin pump is a pager-size compact, computerized device,
which contains a small vial of regular insulin or short-acting insulin
analogue (lispro, aspart, glulisine) or a syringe to be filled with
insulin.
 It is attached by a catheter inserted under the skin, using a small
needle, which is removed. Every two to three days, the catheter
must be changed.
• Recent advances also include quick release tubing to enable patients
to easily disconnect from the pump during activities such as
showering, swimming, and intimacy.
 The pump continuously and automatically delivers small amounts of
regular or short acting insulin every few minutes.
 This is called the basal rate.
•1,4
•Physiological basal insulin
•requirement
•ui
•1,2
•1
•0,8
•0,6
•0,4
•0,2
•0
•0
•1
•2
•3
•4
•5
•6
•7
•8
•9
•10
•11
•12
•13
•14
•15
•16
•17
•18
•19
•20
•21
•22
•23 H
•Basal rate settled through insulin pump
• Figure 4. “Physiological” insulin pump therapy
Basal insulin dose
• Serve to maintain glycemia in target range over night and in
the absence of meals or change in daily activities. The Total
Daily Basal Dose (TDBD) needs to be up to 60% of the Total
Insulin Daily Dose (TIDD). BS of short-acting insulin are
given 30min and rapid-acting insulin 5-15min before meal.
Adjustment of nighttime basal dose is based on 3 a.m and
fasting Blood Glucose (BG) and daytime basal dose according
BG levels when meals are skipped or delayed. Adjustment of
boluses is based on 2-hours postprandial and than pre-meal
BG levels.
MAIN ADVANTAGES
• Maximum flexibility; meals can be skipped
or delayed; no peak insulin activity such as
intermediate and long-acting insulin;
insulin infusion set needs to be changed
every 2-3 days instead of 4 daily injections
(MDII); can be disconnected for specific
activities and substitute with MDII for
short periods.
Other advantages
• More constant and predictable insulin absorption, with a
variability less than 3 %. Both regular insulin and short-acting
analogues appear to provide a more consistent, reproducible
absorption pattern than intermediate insulin suspensions. Insulin
administered by an insulin pump provides the greatest day-today reproducibility and insulin availability, and the least
unexpected fluctuations in glycaemia control,
• Reduced risk of severe and exercise induced hypoglycaemia due
to fact that there is minimal subcutaneous insulin depot, and a
lower temporary basal rate can be settled,
• Improvement or slowing of other metabolic factors and diabetes
complications: diabetic nephropathy, peripheral and autonomic
neuropathy, retinopathy, hypertriglyceridemia and
hypoalphalipoproteinemia, and diabetic changes in transplanted
kidneys.
• An indirect prove of the certain
advantages of insulin pump therapy might
be that more than 50% of healthcare
professionals with type 1 diabetes who are
members of the ADA and American
Association of Diabetes Educators as well
as many professional athletes(?), use
insulin pumps.
MAIN DISADVANTAGES
• High price; wear pump 24h/day; interruption
of insulin infusion due to the pump or infusion
system malfunction cause hiperglycemia and
Diabetic KetoAcidosis (DKA) within hours;
infection at infusion cite.
MAIN FEATURES IMPORTANT FOR
SELECTING OF PUMP TYPE
• Size; type of infusion set; BS and
temporary BR options; display; resistance
to moisture; communication with BG
meter with automatic calculation of BS;
availability of 24h technical assistance and
record of reliability.
Simplicity in your life
• A great body of evidence proved that insulin pump
therapy is associated with significant improvement in
glycaemia control, by reducing the extreme high and low
blood glucose values, and the fasting hyperglycaemia
(“dawn” phenomenon). In the DCCT, 42% of subjects
used CSII during their last full year of study treatment.
They achieved a further reduction of HbA1C with 0.2%
to 0.4% and a significant improvement in lifestyle
flexibility. CSII-treated patients maintained a mean
HbA1c of 6.8 % vs. 7.0 % in MDI-treated subjects
during the trial (p < 0.05).
• Insulin requirements significantly decreased after
switching on insulin pump therapy (pre-CSII:
53.69 ± 0.11 iu/day, or 0.74 ± 0.04 iu / kg / day and
post-CSII: 44.19 ± 0.07 iu/day, or 0.62 ± 0.02 iu /
kg / day; p < 0.001).
 Most of the studies showed a decrease in
frequency of both mild and severe hypoglycaemic
episodes.
• The annual cost for MDI, with lispro and
glargine was 4900 Euro compared to 9373
Euro for pumps.
• Compared to multiple daily injections with
insulin glargine, pump therapy was found
to be similar or even better in youth, in
terms of glycemic control, frequency of
hypoglycaemia or adverse events.
• Total daily insulin dose was unchanged in
the glargine group, but significantly
reduced (p < 0.01) in pump group (1.4
units/kg at baseline vs. 0.9 units/kg).
 The woman with type 1 diabetes considering pregnancy requires an
intensive, flexible insulin program to normalize glucose levels before
conception.
 Good glycemic control during pregnancy is associated with less fetal
macrosomia and fewer neonatal complications.
 Intensive antihyperglycaemic therapy in gestational diabetes is
associated with a lower risk of adverse events and maternal and fetal
complications, as recently demonstrated by ACHOIS (Australian
Carbohydrate Intolerance Study in Pregnancy).
• Insulin pump therapy is ideally suited for these situations due to less
variability in blood glucose levels and the possibility to adjust insulin
doses in order to rapidly improve glycemic control.
Metabolic benefits: reduced frequency of
hypoglycaemia
• Tight glycemic control is associated with an increased
risk for hypoglycaemia, as demonstrated by DCCT. Use
of insulin pump has been proved to reduce the
variability of glucose levels and severe hypoglycaemia in
comparison with MDI, with no discernible reduction in
glycemic control. This decrease in hypoglycaemic events
has been accompanied by an increase in self-reported
warning symptoms of hypoglycaemia, as well as by an
increase in counter regulatory hormonal responses to
hypoglycaemia
 Severe hypoglycaemia has now become an accepted
indication for initiation of CSII therapy, and may
be the greatest advantage offered by CSII.
• Many studies demonstrated a reduced frequency of
hypoglycaemia, a decreased risk of nocturnal
hypoglycaemia and a decreased risk of activityinduced hypoglycaemia.
• An analysis conducted in the United Kingdom
compared the cost-effectiveness of CSII with
that of MDI and found that CSII was most
cost-effective in patients who had more than 2
severe hypoglycaemic events per year and
who required admission to hospital at least
once every year.
Metabolic benefits: weight control
• Intensive insulin therapy followed by
significant improvement of glycemic
control can be associated with weight gain.
Reduced insulin requirements, greater
flexibility in food intake and less
hypoglycaemia might result in minimal
weight gain among patients who use
insulin pump therapy.
Indications for insulin pump therapy (CSII) I
• Insulin pump therapy should be considered for the
management of:
Type 1 diabetes poorly controlled under
conventional multiple insulin injections;
"Dawn” phenomenon or "reverse dawn"
phenomenon (basal rate is higher from 9 PM
to 3 AM and lower from 3 AM to 6 PM in
young children);
– Marked daily variations in glucose levels;
Brittle diabetes;
Hypoglycaemia unawareness or of
hypoglycaemic events requiring assistance;
– Need for flexibility in lifestyle;
Indications for insulin pump therapy (CSII) II
 Pregnancy, pre-pregnancy, gestational diabetes;
– Low insulin requirements (< 20 U/day), extreme
insulin sensitivity;
 Diabetic complications including neuropathy,
retinopathy, who require intense diabetes
management;
– Type 2 DM inadequately glycemic controlled by
multiple daily injections;
– Glycemic control during regular vigorous exercise in
people with type 1 diabetes.
– Diabetics with severe peripheral angiopathy –
gangrene
 Patients who develop DM after pacreatectomy or
after pancreatic or islet transplantation
CSII – in pregnancy
morning
Bolus
afternoon
Bolus
evening
night
B- breakfast
L - lunch
D – dinner
Bolus
Basal rate
B
L
D
sleeping
Female
Bolus: 6 IU + 6 IU + 6 IU
Basal rate: 00-08h - 0.6 IU/h 08-00h - 0.9 IU/h
• Immediately before the transplantation,
they were submitted to intensified insulin
treatment comprising 4 daily doses using
pen (5 patients) or insulin pump treatment
(4 patients) in order to obtain strict
metabolic control, and the treatment was
continued after transplantation at least for
a year.
PATIENTS SELECTION
• Strongly motivated: having necessary cognitive and
physical capabilities to operate the pump safety and
anticipate and evaluate adjustments made in insulin
dosage; patients has demonstrated willingness to
perform glycemic self control; Patient has financial
resources or reimbursement by healthcare
insurance (state, private), sponsors; patients can
quantify food intake: carbohydrate counting and
carbohydrates equivalents.
PROVIDER ASPECTS
• Ideally, CSII therapy should be prescribed,
implemented, and followed by a skilled
professional team familiar with CSII
therapy and capable of supporting the
patients.
“Whole package” of insulin pump therapy
 Therapeutic patient education generally
addressed to diabetes control and specifically to
insulin pump is mandatory.
• It is important patient to understand the real
benefits of insulin pump therapy and to have
realistic expectations.
 Rigorous self-monitoring of blood glucose is also
required.
• Common misconceptions are related to the belief
that:
– the insulin pump will cure the patient’s diabetes
 the patient will have a totally unrestricted free diet
– pump therapy is easy with little or no adjustment
needed
– they will have perfect blood glucose control with the
pump
 the patient will not have to check their blood glucose
levels regularly.
• All these beliefs should be specifically
addressed in the education programme, to
create the real picture of insulin pump
therapy.
Case Report
• Patient J.M; female; 17 y. old, pupil.
• Came in our diabetic department with
• MAIN DISCONFORT: fatigue, thirst,
drinking increased volume of liquid,
increased volume of urine, symptoms and
signs of hypogycaemia
Anamnesis
• Diabetes mellitus type 1 appeared in 9th year, immediate
start of insulin therapy. Due to bad glycoregulation
(HbA1c 11.3%) intensive insulin therapy was
introduced before 6 moths (Actrapid HM and NPH).
• Insulin daily dose: 3 times premeal rapid acting insulin
analogue NovoRapid (25+25+25=75IU) and once long
acting NPH as basal insulin (46IU in the evening, before
sleep).
• TOTAL DAILY DOSE OF INSULIN = 121 IU !!!
• Frequent hypoglycaemia, medium degree
• Keep the diet insufficient
• BMI =26 kg/m2
• Hyperprolactinemia. Amenorrhoea
• Due to this reasons external insulin pump
(MiniMed 508) was introduced (CSII)
• Basal rate 1 IU / h = 24 IU
• Boluses 14+14+14 = 42 IU
• TOTAL DAILY DOSE OF INSULIN = 66 IU
• After 2 month: HbA1c 12%, predominat
hyperglycaemia, rare hypoglycaemia
• Daily profile of glycaemia: 07h 15.0mmol/L
(before breakfast), 2h after 5.0, before lunch
24.9, 2h after 25.6, before dinner 19.4, 2h after
15.6, 24h 14.7, 03h 19.9 mmol/L
• No ketoses
• Multiple insulin injection was introduced again:
• NovoRapid boluses before meal: 18+18+18 IU,
Insulatard 30 IU in the evening.
• TOTAL DAILY DOSE OF INSULIN = 84 IU
Other investigations
• Insulin antibody 13.9% INCEREASED (serum, RIA,
upper normal limit 5.2%)
• IgE antibodies specific for human insulin <0.35 kUA
(normal range 2-100)
• IgA 2.148 gr/L (normal); IgG 10.34 gr/L (normal); IgM
1.24 gr/L (normal) ; Total amount IgE <9.0 kU/L
• Immune complexes: 2.253, INCREASED (normal <0.5)
• The new regime of insulin therapy was
introduced:
• Lantus insulin in the morning 44 IU
• NovoRapid insulin in the morning 14IU and in
the evening 28 IU
• TOTAL DAILY INSULIN DOSE = 72 IU
• Keep the diet further insufficient
• After one month:
• Lantus insulin in the morning 40 IU
• NovoRapid insulin in the morning 14 IU and in the evening
14 IU = 28 IU
• TOTAL DAILY INSULIN DOSE = 68 IU
• Daily profile of glycaemia: mean 9.0 mmol/L
• Rare, mild hypoglycaemia, NOT DURING THE NIGHT
• Better adherence to diet, motivation, education for IIT,
support from family
• Every day 24h contact with our department
Summary I
• Bad glycoregulation in log period of time despite:
• Enormous total daily dose of insulin
• Application of MDII (121 IU) after that CSII (66
IU)
• Immunological insulin resistance: insulin antibodies,
>1 IU/kg of insulin
• Bad adherence to diet, no motivation, education,
support from family
• Insufficient contact with state diabetic care services
Summary II
•
Good effects of insulin analogues:
Lantus insulin (long acting)
NovoRapid (rapid, short-acting)
Total daily dose ≈ 1 IU/kg
One may expect further decrease of total insulin daily
dose
If insulin pump intent to be used again in this patients
rapid, short-acting insulin analogues need to be
introduced (NovoRapid ? Lispro ?)
Conclusion
• Pup therapy (CSII) has many biological,
medical, social limitations especially if
contraindications are not respected
• Insulin analogues may be useful in some
cases of MDII and CSII failure
Aspart vs Lispro vs Regular
CSII in Type 1 Diabetes
N = 146, mean age 38, BMI 25
HbA1c %
Aspart
Base 4 mo
7.34 7.36
Lispro
Base 4 mo
7.29 7.47
PG 90 min after dinner
mmol/l
7.6 (p<0.02)
9.1
Pump or line blockage
No differences
Hypoglycemia
No differences
Bode BW et al. Diabetes;50(Suppl 2):A106
Regular
Base 4mo
7.47 7.63
9.5
NovoRapid® vs human insulin vs insulin lispro
in CSII study: Self-Reported Hypoglycaemia
p<0.05
p<0.05
Episodes/month/patient
12
10
8
6
4
2
0
NovoRapid®
ANA 2024, Data on File
human insulin
insulin lispro
• A retrospective study on 82 adults with type 1
diabetes, duration 19.7 ± 9.9 years, who started
CSII after a MDI regimen with either NPH or
glargine, regular or short acting analogues showed
that after 3 months of CSII, HbA1c significantly
decreased, 8.35 ± 1.06 % vs. 9.39 ± 1.35%, (p <
0.001) and the reduction was maintained over the
whole CSII treatment.
• Significant decrease of severe hypoglycaemic
episodes (0.35 ± 0.07 per patient/year during MDI
vs. 0.10 ± 0.02 during CSII, p < 0.001) and insulin
requirement (52.1 ± 17.5 units/day vs. 38.8 ± 12.3, p
< 0.001) have been found.
• According to this study, older age and higher
baseline HbA1c predict the better glycemic
improvement.
STARTING INSULIN DOSE
• Firstly, reduce TIDD on MDII by 25-30%. Staring dose must
be individualized for each patient. TDBD should be 40-60% of
TIDD (divide by 24 to obtain hourly BR, usual range 0.5-2.0
U/hour for type 2 diabetics). TDBD can be calculated by
multiplying the patients weight in kg by 0.3 (divide by 24 to
obtain hourly BR). Higher BR from 3-9am, intermediate
during the day, lower at bedtime. For pre-meal BS (from
TDBD): breakfast 20%, lunch 10%, supper 15%, bedtime 5%.
Calculation based according to patient’s sensitivity (i.e. 0.5-2.0
U/15g carbohydrate). Adjusted BR and BS by 10-20% based
on BG readings before and after meals, at bedtime and at
3am. All patients on IIT should be provided with correction
BS or supplemental BS guidelines to correct out-of-range BG
values, using the 1700 rule.
PUMP MALFUNCTION
 If it occurs, use usual dose of short or rapid-acting insulin
before meals and long-acting insulin at bedtime.
 If the patients wish to disconnect pump it is possible up to 2
to 4 hours without any adverse consequences.
 For the period longer than 4 hours the usual basal-bolus
therapy should be given.
 The dose of the long-acting Glargine will be equal to TDBD.
• It is important to teach patients to adjust short or rapidacting insulin for variations in food intake and to adjust
insulin for exercise
• PREVENTION OF HYPERGLYCEMIA AND
HYPOGLYCEMIA as well must be performed
continuously. HYPERGLYCEMIA>13.9mmol/l must
be treated to prevent DKA especially during
pregnancy.
• TO PREVENT HYPOGLYCEMIA educate patient
and family; teach patient a systemic approach to
matching insulin to food intake and change in routine;
patients should check BG levels at least 4 times daily
(before meals and bedtime), weekly at 3am, before and
after exercise, every 2 hours during illness, before
driving reach BG values>80mg/dl; bedtime snacks
consisting protein and carbohydrate to avoid
nocturnal hypoglycemia.
SAFETY
• CSII with pump is as safe as MDII when
recommended indications and procedure are
followed. Undetected interruptions in insulin
delivery may result in ketotic episodes more
often and more quickly with CSII which is of
particular concern in pregnancy. Infections
or inflammation at the needle cite may occur
also.
CSII EVOLUTION
• Pump therapy in type 1 diabetics starts in
1970’s. Since than, pumps have become much
smaller more durable and easier to use.
Modern pump have electronic memory,
multiple BR, different BS options, safety
alarms and remote controls. New software
permitted the correction BS for an out-ofrange BG level and how much insulin to give
for a certain amount of carbohydrate.
FUTURE OF PUMP THERAPY
• Once continuous glucose monitoring is
available, the effectiveness of pump therapy in
achieving near-normal glycemia will be
enhanced and patients than may avoid
hypoglycemic or hypoglicemyc episodes.
Almost the final steps will be closed-loop
systems as an external or implantible feeding
back to an external or implantable pump.
• Sonor
• Com-station
• Monitor
• Softwere
NEW THERAPEUTIC AREA FOR
EXTERNAL PUMPS
• For type 2 DM the CSII is used also. But, whether
it is ever necessary or advantageous compared
with a less complex treatment is unknown.
Nevertheless, in these patients much lower risk of
hypoglycemia exists. Some studies showed that
the glycemic control may be as good as or better
than with MDII regime. Recent results shoved the
benefit of short term CSII in the case of
secondary failure of per oral therapy and in
newly diagnosed type 2 DM
Conclusions I
 In most patients, mean blood glucose levels and glycated
haemoglobin A1c are either slightly lower or similar on CSII
versus MDI;
 Hypoglycaemia is markedly less frequent than during intensive
injection therapy;
 Diabetes ketoacidosis occurs at the same rate;
 Nocturnal glycemic control is improved with insulin pumps;
 Basal rate changes help to minimize the "dawn phenomenon“;
 Insulin pump therapy is safe and effective in children and
adolescents, where fewer episodes of severe hypoglycaemia have
been found, with no increase in ketoacidosis while maintaining the
glycemic control. One of the particular benefits of CSII in infants
and toddlers is its ability to reduce the risk of severe
hypoglycaemia. Even limited use of CSII for overnight basal
insulin replacement in children 7 to 10 years of age has been shown
to be effective.
Conclusions II
 The small age of the patient should not, itself, be a barrier to
initiation of this therapy.
 Use of lispro, aspart or glulisine in CSII is particularly suitable for
infants and toddlers, who have unpredictable appetites and eating
patterns, because it can be administered either before or after meal,
depending on the amount of carbohydrate that is eaten;
• A successful therapy with CSII involves the appropriate selection,
evaluation and training of individuals, a skilled and motivated health
care team and close contact between the pump user and the health
care team.
 CGMS usage serves to optimize therapy and metabolic control in
patients children and adults, with type 1 Diabetes mellitus, and CSII.
CGMS provides a new level of protection against dangerous
hyperglicaemia and especially hypoglicaemia. CGMS is an very
important part of CSII now in even more in the future.