Effect of adding vildagliptin to start of insulin treatment in patients with type 2 diabetes

Type 2 diabetes is characterized by progressive beta cells, causing
deterioration of beta cell function. Due to this progressiev nature of the
disease, at a certain point oral glucose lowering drugs in combination with
diet cannot establish normoglycemia anymore. At this poit the patient should
start insulin treatment. Usually once daily long-acting insulin is then
started. Insulin treatment usually results in weight gain and increases the
change for hypoglycemia.
A lot of research looks into the effect of oral glucose lowering drugs added to
insulin on HbA1c, as a measure of glycemic regulation. Studies with
DDP4-inhibitors showed, significant reduction of HbA1c , when added to insulin,
where the insulin regimen was kept the same. This was seen in combination with
less hypoglycemias. But in daily clinical practice insulin regimens will be
modified according to glycemic variation, and not HbA1c but insulin doses are
the primary effect.
The mechanism of better glycemis control of combination of DPP4-inhibitors and
insulin includes a glucose dependent insulin secretion (in contrast to for
instance sulfonyl ureum derivates, which give a constant beta cel stimulation,
unrelated to glucose) with the DPP4-inhibitors, as well as decreases in
glucagon production (hyperglucagonemia is a problem in diabetes). Resulting in
less endogeneous glucose production.
The primary effect of this study will be the necessary dose of insulin
required. Secundary end points are parameters related to glucose regulation
(continuous glucose measurement CGMS), insulin and glucagon levels after
standardized mixed meal tests, vascular effects (24 hours blood pressure
measurement, lipids), changes in advanced glycation end products (AGEs,
measured by skin autofluorescence).

Is addition of a DPP4-inhibitor (vildagliptin) beneficial in type 2 diabetic
patients, starting on once daily long-acting insulin in combination with 2 dd
metformin. Primary end point is necessary dose of insulin to remain glycemic
control. Secundary end points are hypoglycemia, weight, glucose variability,
parameters after mixed meal test and cardio-vascular parameters.

Patients with type 2 diabetes are randomized between insulin and metformin
treatment with vildagliptin and insulin and metformin treatment with placebo.
The following parameters are measured at the begin and at the end of the study:
Primary parameter:
- required insulin dose
Secondary parameters:
- weight
- hypoglycemias
- glucose variability
- insulin and glucagon levels after mixed meal test
- HbA1c, fructosamine
- 24 hours measured blood pressure
- lipid profile
- markers of vascular function, inflammation and coagulation
- advanced glycation end products measured by skin autofluorescence

Normal insulin treatment with fixed dose metformin, combined with vildagliptin
(intervention group) or placebo (control group).

The insulin treatment itself is the same as usual. But metformin is given as a
fixed dose (2 dd 850 mg) and all other oral antihyperglycemic agents are
discontinued in this study. Patients should attend the outpatient clinic more
often (4 times). The only study so far combining insulin and vildagliptin
showed a good tolerability and significant less hypo's in the patients taking
vildagliptin. Based on this prior study we expect the risk for patients taking
a combination of vildagliptin and insulin to be low. Furthermore in patients
with deteriorating glycemic controol (hbA1c + > 1.0%) the study will be
stopped.
The secondary parameters require a few more tests, which gives the extra
burden, consisting of:
- the continuous glucose monitoring system (requires patients to have a small
subcutenuous needle attached to a monitoring device for 72 hours), this device
is also used in daily clinical practice to optimize glucose control
- 24 hours blood pressure measurement (requires the patient to wear a blood
pressure band, measuring the blood pressure every 30 minutes for 24 hours),
again this is frequently used in daily clinical practice
- AGE-reader (a device that illuminates the fore arm for a few seconds with
ultraviolet light)
- mixd meal test (continuous blood sampling during 3.5 uur in the outpatient
clinic)