Better Accepance of a Singe injection Apidra (insulin glulisine) Added to once daily Lantus (insulin glargine) versus twice daily Premixed insulin in a real Life Use Setting.

Results of landmark studies such as the DCCT for diabetes mellitus (DM) type 1
and the UKPDS for DM type 2 showed that good glycemic control results in a
significant reduction in microvascular complications.1,2 Long-term follow-up
extensions of these studies also revealed that early intervention and good
glycemic control early in the disease process, will result in a long-term
reduction in macrovascular complications.3,4 Furthermore, beta-cell function
will progressively worsen over time, with a concomitant deterioration of
glycemic control.5 This progressive nature of the disease process will make
intensification of therapy, including insulin therapy, the rule and not the
exception.6,7 Guidelines, such as the Dutch Primary Care Guideline Diabetes
mellitus type 2, emphasize such a step-wise approach, with the addition of once
daily basal insulin when treatment goals can not be met with oral blood glucose
lowering drug (OGLD) alone.8 When further intensification of insulin therapy is
indicated, the Dutch GP guideline describes two alternative regimens: the
addition of mealtime insulin at each meal in a basal/bolus regimen or switch to
a twice daily regimen with premixed insulin or NPH-insulin. Although the GP
guideline does not give preference to either regime, it does state that a
basal/bolus regime is more flexible and more in line with the pathophysiology
of the disease. Indeed a previous study showed that more patients reach a HbA1c
below 7% on a basal/bolus regime compared to twice daily premixed insulin in
patients controlled on basal insulin plus OGLD.9 Although a basal/bolus regime
is considered to be the *golden standard*, many patients and practitioners
unfortunately do not choose this option because of a perceived fear for
multiple insulin injections and concomitant glucose monitoring, hypoglycemia or
weight gain.10

In the recently updated ADA/EASD consensus statement an alternative approach is
used to intensify insulin therapy for those patients where good glycemic
control is no longer achieved with once daily basal insulin plus OGLD.11 When
basal insulin is titrated sufficiently to adequately control fasting blood
glucose levels (i.e. a fasting blood glucose of 4-7 mmol/L), but overall
glycemic treatment goals are not met (i.e. HbA1c > 7%), a rapid acting mealtime
insulin is added before a selected meal to reduce postprandial glucose
excursions. To select the meal with the largest glucose burden, blood glucose
is checked before lunch, dinner and bedtime. Depending on these results a
single injection of rapid acting insulin is added before breakfast, lunch or
dinner respectively, with a starting dose of 4 U. Subsequently the insulin dose
is adjusted by 2 U every 3 days until the 2 hour postprandial blood glucose is
in range (i.e. < 9 mmol/L). If persistent hyperglycemia (HbA1c > 7%) requires,
the insulin regimen can subsequently be extended with a second or even third
injection mealtime insulin, until a complete basal/bolus regimen. This so
called basal plus regimen permits a simple step-wise approach to intensify
insulin therapy for those patients inadequately controlled on basal insulin and
OGLD. With this basal plus alternative a switch to a different twice daily
premixed regimen may become unnecessary. Since previous studies have shown that
the use of premixed insulin preparations results in more hypoglycemic events,
higher insulin doses and more weight gain than insulin glargine (Lantus®) +
OGLD, this may have positive implications on patient acceptance for further
insulin therapy intensification.12, 13, 14, 15
One of the first trials to study the step-wise basal plus approach has recently
been published.16 In this study with 393 patients with DM type 2, fasting blood
glucose was within range on insuline glargine (mean FBG 6,8 mmol/L), but
overall hyperglycemia was suboptimally controlled (mean HbA1c of 7,3%). The
addition of a single injection of insulin glulisine (Apidra®) before breakfast
or the main meal resulted in a significant improvement in glycemic control with
a mean HbA1c < 7% after 24 weeks of treatment and 30,7% of the patients
achieving a HbA1c level <= 6,5%. The improvement in glycemic control is
primarily due to an increase in insulin glulisine dose and does not come at the
expense of increased basal insulin dose, weight gain or high hypoglycemic event
rate.

The objective of this observational, randomized study is to examine the
efficacy, safety and patient acceptance of the basal plus insulin regimen (i.e.
one injection rapid acting insulin glulisine at the main meal added to once
daily basal insulin glargine) in daily practice in patients with DM type 2 in
The Netherlands.

National, open, multi-center, prospective (26 weeks), randomized, parallel
phase IV clinical study

This study consists of two parts: a screenings period of 2 weeks, and a
treatment period of 24 weeks. During the screenings period the patients will be
asked to determin their fasting blood glucose levels 5 times in the week prior
to the baseline visit. The middle value of the 5 taken samples will determin if
the patient can continue with the study or not.

If the patient continues in the studie, he/she will be asked to perform 2
7-point measurements of their blood glucose levels in the week prior to the
next visit. This will be noted in the patient diary.

At visit 2, 4 and 5 the patients are asked to fill in treatment satisfaction
questionaires. The estimated time they will need for this is 15 minutes at
visit 2 and 4 and 20 minutes at visit 5.

The patient will see the doctor a total of 5 times during the 6 month period.

The side-effects expected to be seen are no different to any other side-effects
expected with insulins. The most common side effects are hypo- and hyper
glyceamias and gain in weight.