Download Insulin therapy in type 2 diabetes mellitus

1
Dr . Ghadiri , MD
Assistance professor of endocrinology
Shahid Sadoughi
University of Medical Sciences
2
 The importance of glycemic control in minimizing
complications related to diabetes has been well
established in type 1 diabetes .
 United Kingdom Prospective Diabetes Study
(UKPDS) demonstrated that strict glycemic control in
patients with type 2 diabetes results in a similar
reduction in risk of microvascular disease .
3
 Normoglycemia is now the goal for many patients with
type 2 diabetes.
 However, target A1 C levels in patients with type 2
diabetes should be tailored to the individual, balancing the
improvement in microvascular complications with the risk
of hypoglycemia.
4
 Initial therapy should begin with diet, weight
reduction, and exercise, which may
normoglycemia if compliance is optimal.
induce
 Metformin therapy may be initiated, concurrent with
lifestyle intervention, at the time of diabetes
diagnosis.
5
 Oral agents become less effective as beta cell function
declines. The therapeutic options for patients who fail
initial therapy with lifestyle intervention and
metformin are to add a second oral or injectable
agent, including insulin, or to switch to insulin.
 There is no consensus on which option is most
effective.
 However,
insulin is the preferred second-line
medication for patients with A1C >8.5 percent or with
symptoms of hyperglycemia despite metformin
titration.
6
NORMAL PATTERNS OF
INSULIN SECRETION
 Insulin is secreted in a pulsatile manner; pulses occur
under basal conditions and in response to meals .
 Basal insulin secretion represents approximately 50
percent of 24-hour insulin production, with the
remainder accounted for by prandial (mealtime)
excursions.
7
8
Basal Insulin
In person without diabetes, the pancreas
delivers a small amount of insulin continuously
to cover the body’s non-food related insulin needs.
9
Bolus Insulin
The amount of insulin required to cover the
food you eat.
Rapid-acting or Short-acting
insulin works as a Bolus Insulin
10
 Intensive insulin therapy has been used to describe
complex regimens that separate basal insulin delivery
(given as one to two daily injections of intermediate
or long-acting insulin) with superimposed doses of
short or rapid-acting insulins three or more times
daily.
11
INSULIN PREPARATIONS
In type 2 diabetes, insulin is generally provided in two
ways:
 Basal
supplement to suppress hepatic glucose
production and maintain near normoglycemia in the
fasting state.
 Pre-meal bolus dose of short-acting or rapid-acting
insulin to cover the extra requirements after food is
absorbed.
12
13
 For many patients with type 2 diabetes, a basal
supplement is often adequate for good glycemic
control as endogenous insulin secretion will control
the post-prandial excursions.
 Some patients with type 2 diabetes will require
additional premeal boluses, similar to treatment for
type 1.
14
Premixed insulin preparations
 Most premixed (biphasic) preparations contain
an intermediate acting insulin and either a short or a
rapid-acting insulin.
 Some patients who require pre-meal insulin in
addition to basal insulin prefer premixed insulins for
convenience.
15
 Premixed preparations offer little glycemic advantage
compared with adequately titrated basal and bolus
insulin .
 In
a meta-analysis of trials comparing rapidacting/intermediate premixed insulin preparations
with other treatments (premixed regular/NPH insulin,
long-acting insulin, and non-insulin agents), premixed
rapid-acting preparations were similarly effective in
reducing
A1C
levels
as
premixed
regular
insulin preparations .
16
 Compared with other insulin therapy (long-acting or
regular/NPH mix), premixed rapid-acting insulin
preparations were more effective in reducing
postprandial blood glucose levels but less effective in
reducing fasting blood glucose.
 Premixed rapid-acting preparations were more often
associated with minor hypoglycemia and weight gain
than long-acting insulin or oral agents.
17
 Premixed insulin preparations are sometimes used in
type 2 diabetics, but we almost never use them in
patients with type 1 diabetes.
 For patients with type 2 diabetes who require prandial
insulin, the goal is to adjust the dose of fast-acting
insulin immediately prior to a meal, and therefore, we
prefer to keep basal and premeal insulin injections
separate and adjust them independently.
18
COMBINATION ORAL AGENT
AND INSULIN THERAPY
 Patients with persistent hyperglycemia despite oral
hypoglycemic therapy may add insulin to oral
medication or may stop the oral drug(s) and begin
insulin.
 The rationale for combination oral hypoglycemic drug
and insulin therapy is that, by suppressing hepatic
glucose production, the patient can retain the
convenience of oral agents, while minimizing total
insulin requirements .
19
 Many studies have shown that glycemia improves with
insulin combination therapy .
 In some studies, target A1C goals (≤7 percent) were
achieved in 60 to 70 percent of subjects .
20
Choice of insulin
 When insulin is combined with oral agents, a basal
(long- or intermediate-acting) rather than a shortacting premeal (prandial) insulin is a reasonable first
choice.
 The addition of basal insulin will improve nocturnal
and fasting blood sugar, whereas premeal bolus
insulin will decrease postprandial glucose excursions.
21
Basal insulin
 While intermediate-acting NPH insulin has been used
commonly at bedtime to supplement oral
hypoglycemic drug therapy, longer acting insulins,
such as insulin glargine (once daily) and detemir (once
or twice daily), added to oral agents are equally
effective for reducing A1C values and may cause less
nocturnal hypoglycemia.
22
 In contrast to NPH, the time-action profile for insulin
glargine has virtually no peak ,which makes it an
acceptable basal insulin preparation for intensive
insulin therapy.
23
 Insulin detemir :
Long-acting insulin analog; a fatty acid side chain that
allows albumin binding results in prolongation in
action. However, its duration of action appears to be
substantially shorter than that of insulin glargine .
24
 Meta-analyses of trials in patients with type 2 diabetes
comparing once-daily insulin glargine or detemir to
once or twice-daily NPH insulin report similar
glycemic control between groups .
 Insulin glargine and detemir may have some relatively
modest clinical advantages over NPH (less
symptomatic and nocturnal hypoglycemia) with the
important disadvantage of high cost.
25
Premeal (prandial) bolus insulin
 For patients with type 2 diabetes, a basal supplement is
often adequate for good glycemic control, but for
others, premeal (prandial or preprandial) boluses are
necessary as they are in type 1 diabetes.
26
 The newer rapid-acting insulins may have a minor
glycemic advantage over short-acting (regular) insulin
in patients with type 1 diabetes, but they do not have a
clinically significant advantage in patients with type 2
diabetes .
 No significant differences were seen in serum A1C
concentrations or the number of hypoglycemic
episodes.
27
 However, the ability to inject the rapid-acting insulins
immediately before meals, as opposed to the 30 to 45
minutes before the meal recommended for short
acting insulins, may provide improved convenience
for patients.
28
Comparison of insulin regimens
 A number of randomized trials have evaluated
different insulin regimens in patients with type 2
diabetes.
 These trials primarily used glycemic control as the
endpoint; data are more limited on cardiovascular
outcomes.
29
Basal versus prandial
 Both basal and prandial regimens are similarly
effective in reducing A1C concentrations when insulin
doses are aggressively titrated to achieve glycemic
goals.
30
 This was illustrated by a randomized trial of once daily
insulin glargine versus prandial insulin lispro in 415
patients who were inadequately controlled with
metformin and a sulfonylurea .
 There were similar improvements in A1C and target
A1C concentrations between 6.5 and 7.0 percent were
achieved by 27 and 30 percent of subjects, respectively.
Basal insulin was associated with greater patient
satisfaction and less hypoglycemia.
31
Basal or prandial versus
premixed
 Premixed insulin regimens with fixed combinations of
short or rapid acting insulin with long or intermediate
acting insulin claim to provide two peaks of insulin
activity from just one injection, although in practice
the peaks from the rapid acting and intermediate
acting insulins tend to merge together and form a
single peak of insulin action.
32
 In a three-year trial, 708 patients with type 2 diabetes
who were suboptimally controlled with metformin and
a sulfonylurea were randomly assigned to premixed
biphasic insulin aspart (twice daily), prandial insulin
aspart (three times daily), or basal insulin
detemir (once or twice daily) .There was no difference
in median A1C levels among the three groups, but
significantly more patients in the basal and prandial
groups achieved an A1C level of ≤6.5 percent than in
the biphasic premixed group .
 Patients in the basal group had the fewest episodes of
hypoglycemia.
33
 Conclusion :
Whether a basal or a prandial (premeal) bolus strategy is
more effective in improving important diabetes
endpoints
(microvascular
and
macrovascular
complications) remains uncertain.
In the absence of such data, we prefer initiating basal
insulin, rather than prandial insulin, in patients who are
poorly controlled on oral agents .
For patients who require prandial insulin, we prefer to
keep basal and prandial insulin injections separate and
adjust them independently.
34
Insulin dose
 Basal
 Bedtime dose of NPH, detemir, or glargine insulin is
being added to oral drug therapy:10 units or 0.2 units
per kg (taken at 10:00 PM).
 Fasting blood glucose (FBG) should be measured
every day. An increase of 2 to 4 units in the bedtime
insulin dose should be made periodically
(approximately every three days) if the mean FBG is
above 130 mg/dL during this time .
35
 In this way, the bedtime insulin dose can be titrated
over a period of several weeks or months. If fasting
glucose levels are very elevated (>250 mg/dL), or if a
patient is known to be very insulin resistant, initial
doses can be higher and titration more aggressive.
36
Bolus
 If premeal bolus insulin needs to be added, the optimal
dose depends upon many factors, including current and
target blood glucose values, carbohydrate content of the
meal, and activity.
 A typical starting dose is approximately 4 to 6 units.
The dose can be increased by 2 to 3 units every three
days until the postprandial blood glucose target is
achieved.
37
Optimal timing of insulin dose
 For patients with type 2 diabetes on combination
therapy (oral hypoglycemics and once-daily insulin),
the optimal timing of the insulin dose depends in part
upon the type of insulin. NPH insulin may be most
effective if given at bedtime .
 Bedtime NPH : Less weight gain
38
 In contrast, a morning rather than a bedtime dose of
insulin glargine may provide better glycemic control in
patients with type 2 diabetes who are also treated with
an oral agent.
 Nocturnal hypoglycemia was less frequent with morning
and bedtime insulin glargine than with bedtime NPH.
39
 For patients with type 2 diabetes taking an oral
hypoglycemic agent, the optimal timing is oncedaily NPH or detemir at bedtime or once-daily
insulin glargine in the morning or bedtime.
40
SWITCHING TO INSULIN
MONOTHERAPY
 Patients with persistent hyperglycemia despite oral
hypoglycemic therapy may stop the oral drug and
begin insulin monotherapy.
 This approach is cheaper than combined therapy
(although generic metformin is relatively inexpensive),
but results in more weight gain and more episodes of
hypoglycemia.
41
Starting dose
 The initial dose of insulin in patients with type 2
diabetes switching to monotherapy is similar to the
starting dose described above for patients adding
insulin to oral hypoglycemic therapy .
42
 Among patients who are taking insulin and have A1C
values above the desired target, diet and exercise
patterns should first be reviewed. Insulin doses should
then be adjusted to achieve target levels of glycemia.
 Patients should measure blood glucose two to four
times daily and should only reduce their insulin dose if
hypoglycemia develops.
43
 In general, dietary indiscretion and/or inadequate
doses of insulin underlie the apparent failure of many
patients treated with insulin regimens. Daily insulin
doses typically exceed 65 to 100 units per day, and may
sometimes be much higher, before obese type 2
diabetic patients can achieve near-normal glycemia.
44
Once-daily regimens
 For patients receiving insulin monotherapy, a once-
daily dose of intermediate- or long-acting insulin is
sometimes sufficient .
 As an example, insulin glargine is effective when used
alone for once-daily therapy in patients with type 2
diabetes and may be associated with less nocturnal
hypoglycemia and less weight gain than NPH .
45
 However, serum insulin concentrations over a 24-hour
period may be more stable in patients taking two
doses daily, when the insulin preparation is NPH or
detemir .
46
Twice-daily regimens
 If the goal is control of persistent hyperglycemia with a
regimen that is simple, then twice-daily NPH insulin will
be effective in many patients. If excessive postprandial rises
in blood glucose are a concern, then a short- or rapidacting insulin must be added.
 Injection of regular plus NPH insulin before breakfast and
before dinner results in four peaks of insulin action,
covering the morning, afternoon, evening, and overnight .
 However, the peaks tend to merge. Furthermore, with the
common practice of drawing up both insulin preparations
in the same syringe, serum insulin peaks become less
distinct.
47
Intensive insulin
 Use of an intensive insulin regimen (similar to that used in
T1DM) results in higher serum insulin concentrations and
better glycemic control than that achieved with either an
oral drug or conventional insulin therapy alone .
 A potential problem is the weight gain (8.7 kg in one
study) that can occur with intensive regimens that achieve
near normal glycemia .
 This weight gain may in some instances result in partial
noncompliance with therapy, particularly in women.
48
INSULIN AS INITIAL
THERAPY
 An alternative that may be beneficial, but is not widely
used, is a brief period (two to four weeks) of intensive
insulin treatment at the onset of type 2 diabetes .By
inducing near normoglycemia with intensive insulin
therapy, both endogenous insulin secretion and insulin
sensitivity improve .
 The improvement in insulin secretion is presumably due to
the elimination of the deleterious effects of hyperglycemia
on beta cell secretory function, and in some patients, it
results in better glycemic control that can then be
maintained with diet and exercise for many months
thereafter.
49
 Insulin should be particularly considered for patients
presenting with A1C >10 percent, fasting plasma
glucose >250 mg/dL , random glucose consistently
>300 mg/dL , ketonuria, or with unplanned weight
loss in association with hyperglycemia.
50
Continuous subcutaneous insulin
infusion (insulin pump)
 With pump therapy, basal insulin is supplied in the
form of a continuous infusion (comprising between 40
and 60 percent of the total daily dose) with pre-meal
bolus doses given to minimize postprandial glucose
excursions.
51
52
Choice of insulin
 Only short-acting insulin (regular) or rapid-acting
insulins are used with continuous therapy. In a doubleblind crossover trial, insulin lispro, compared with
regular insulin, resulted in greater reduction in
postprandial blood glucose concentrations ,lower A1C
,fewer episodes of hypoglycemia, and less weight gain .
 Rapid-acting insulin analogs are typically preferred
over regular insulin for continuous insulin therapy.
53
 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 (60 kg woman approximately 0.6 to 0.9 units
per hour). The basal rates are adjusted empirically
based on glucose monitoring results.
54
 Certain time periods during the day may require
higher, while other periods may require lower, infusion
rates depending on individual factors including
lifestyle.
 Most pumps allow for pre-programmed changes in
basal rate to accommodate these requirements.
55
 The premeal bolus dose should be based upon the
carbohydrate content of the intended meal and the
blood glucose level immediately before the meal.
56
Advantages
 CSII is increasingly used in the pediatric population.
 A randomized trial in 32 children and adolescents
(aged 8 to 21 years) with type 1 diabetes showed that
lower A1C and premeal glucose levels were more
achievable with continuous subcutaneous insulin
infusion than with an insulin regimen using once daily
insulin glargine and premeal insulin aspart .
57
 In some children with type 1 diabetes who have
frequent and severe nocturnal hypoglycemia, use of an
insulin pump at nighttime only (with pre-breakfast
NPH insulin and three pre-meal doses of insulin
lispro during the day) can improve overall glycemic
control and reduce hypoglycemia .
58
 Another advantage of insulin pump therapy is that it
allows more flexibility in the timing of meals. If
someone has taken NPH insulin before breakfast, its
action is likely to be maximal around lunchtime or
early afternoon. Thus, delaying lunch can lead to
hypoglycemia. With continuous therapy, the steady
basal infusion should maintain normoglycemia but
not induce hypoglycemia.
59
 In addition, insulin absorption with pump therapy is
less variable from day to day ,and therefore blood
glucose profiles may be more predictable. Both the
small subcutaneous depot and the constancy of the
injection site and depth for the two to three days with
each catheter contribute to the relative consistency of
absorption.
60
 Continuous subcutaneous insulin has also been used
in conjunction with a continuous glucose
monitoring (CGM) device to give the patient more
information about their blood glucose levels and allow
them to make better informed decisions about insulin
dosing. This approach is known as sensor-augmented
insulin pump therapy.
 CSII
in conjunction with continuous glucose
monitoring may effectively improve glycemia while
limiting the rise in hypoglycemia that often
accompanies improved glycemic control.
61
62
Disadvantages
 The costs of the pump and supplies are higher than
those of ordinary syringes and needles.
 Superficial infection.
 System failure is usually due to blockage or leakage in
the syringe or the infusion set or connectors, causing
an interruption of infusion flow .
 Since the subcutaneous depot is so small, any
interruption in continuous flow leads very quickly to
hypoinsulinemia, hyperglycemia, and possibly diabetic
ketoacidosis.
63
64
65
 Finally, many patients prefer not to have to wear a
device and be "tethered" to the pump at all times.
 Pump-treated patients can take off the pump for brief
periods. Doing so for one hour or less does not usually
lead to loss of blood glucose control. For longer
periods (such as overnight), a subcutaneous dose of
intermediate-acting insulin should be given in a dose
1.5 to 2 times the calculated basal infusion rate for that
period .
 Some patients also like to stop pump therapy and use
multiple daily injection therapy for more prolonged
periods, such as summer vacations, to allow water
activities. These transitions are usually easy to make if
planned ahead of time.
66
 The overnight rate can be adjusted to maintain the
pre-breakfast blood glucose in the target range. When
changing the subcutaneous basal insulin infusion rate,
a delay in the actual increase or decrease in plasma
insulin levels must be taken into account, based on the
kinetics of absorption and time to reach a new steady
state .Therefore, basal rates of rapid-acting insulin
should be changed about two to four hours before the
change in plasma level is required.
67
 When converting a patient from a multiple daily
insulin regimen to continuous insulin therapy, the prepump level of chronic glycemia will help determine the
pump basal rate and pre-prandial scales chosen.
 Patient who has been well controlled on his previous
multiple injection regimen (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.
68