Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT00696982 |
| Other study ID # |
shlomit9 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
June 11, 2008 |
| Last updated |
June 12, 2008 |
| Start date |
June 2008 |
| Est. completion date |
June 2009 |
Study information
| Verified date |
June 2008 |
| Source |
Assaf-Harofeh Medical Center |
| Contact |
Shlomit Koren, MD |
| Phone |
972-546-888-385 |
| Email |
shlomitks[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
Israel: Israeli Health Ministry Pharmaceutical Administration |
| Study type |
Interventional
|
Clinical Trial Summary
Recently a new category of antihyperglycemic therapy aiming to modulate the incretin system
has emerged. These drugs induce insulin secretion without inducing hypoglycemia. The effect
of the incretin modulators drugs on hypertension, arterial stiffness, inflammation and
oxidative stress parameters have not been fully investigated yet.GLP-1 analogue has been
suggested to have an effect on endothelium and the development of hypertension. Nystrom et
al have demonstrated that GLP-1 improves endothelial dysfunction in a small group of type 2
diabetes subjects, with coronary heart disease. We hypothesize that DPP-4 inhibitor will
have an effect on hypertension and arterial stiffness by effect on the NO pathway.The aim of
this study is to investigate the effect of two insulin inducers drugs, sulfonyl urea and
DPP-4 inhibitor on 24 hours blood pressure monitoring, arterial stiffness, oxidative stress
and inflammation.
Description:
Background:
Recently, a new category of hypoglycemic therapy has emerged, aimed to modulate the incretin
system in diabetic patients. Compared to other drugs that induce insulin secretion, these
agents do not cause hypoglycemia. However, until now the differential effects of incretin
modulators and the classical insulin inducers on hypettension, arterial stiffness,
inflammation and oxidative stress parameters have not been yet investigated.
Incretins The increase in plasma insulin levels following oral administration of glucose
usually exceeds the levels observed after intravenous glucose administration. The phenomenon
is defined as incretin effect and has been attributed to the intestinal hormones which are
released after oral glucose administration. The two most important incretin hormones are
glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1).
Incretin effect is reduced in type-2 diabetic patients. After oral glucose administration,
both GIP and GLP-1 are secreted and rapidly inactivated by an enzyme dipeptidyl peptidase 4
(DPP-4). Accordingly, the half-life of active GLP-1 is less than 2 min (2). Both GIP and
GLP-1 stimulate insulin secretion in a glucose-dependent manner. Moreover, GLP-1 has also
been shown to increase islet cell neogenesis and differentiation, as well as reduce
apoptosis of β-cells in rodents. (3-5). Incretins also affect glucagon secretion. GIP
stimulates glucagon production (6) ,whereas GLP-1 inhibits synthesis of the latter (7).
Differential effects of the two peptides on glucagon secretion may prove responsible for
normalization of blood glucose after intravenous injection of GLP-1 but not after
administration of GIP or its derivatives [7, 8]. Therefore, GLP-1 is the only incretin that
has been applied for treatment for diabetes.
In addition to its direct insulin/glucagons activities, GLP-1 has other extra-pancreatic
effects:
- It inhibits gastric emptying and small bowel motility , the effects being dependent on
nitric oxide (NO) (8).
- It induces satiety through a central nervous system mechanism (9).
- There is some data suggesting that GLP-1 infusion improves LV function .
- rGLP-1 infusion significantly attenuated the development of hypertension in Dahl Salt
sensitive rats [11]. In patients with type 2 DM, exenatide treatment for 2 years also
resulted in improvement of blood pressure [12]
- GLP-1 exerts direct beneficial effects on endothelium-dependent vasodilatation in
healthy non-diabetic non-smoking normotensive subjects [13].
- In type 2 diabetic subjects with coronary heart disease, GLP-1 infusion significantly
increased relative changes in brachial artery diameter (i.e. improved endothelial
dysfunction) [14].
Since the main limitation of GLP-1 from the pharmacokinetic point of view is its rapid
inactivation by DPP- 4, two strategies have been developed. One strategy is the development
of GLP-1 receptor agonists (GLP-1 mimetics) which are resistant to DPP-4, such as exenatide
(Byetta). The other approach is to prevent inactivation of GLP-1 by inhibiting the DPP-4
enzyme activity.
DPP-4 inhibitors Mice with a genetic deletion of DPP-4 have increased glucose tolerance
following oral glucose administration in association with augmented insulin secretion. [15]
DPP-4 inhibitor in animal studies was shown to augments the active GLP-1 concentration,
increase insulin secretion and improve glucose tolerance. [16, 17] Previous rodent studies
have found that GLP-1 and its analogues may increase beta cell mass by stimulating islet
neogenesis and differentiation and inhibiting apoptosis.[3]. Similar effect can be produced
by DPP-4 inhibition [18, 19].
Sitagliptin Sitagliptin is one of the two most studied DPP-4 inhibitors (the other one being
vildagliptin). It is a competitive reversible inhibitor of the enzyme.[20] It is an orally
active drug that can be absorbed rapidly and efficiently. Hepatic insufficiency does not
seem to alter the pharmacokinetics of this drug, however, renal insufficiency increases
circulating levels of sitagliptin. [21] Sitagliptin proved to be a well tolerated and safe
drug, both for monotherapy and for combination therapy with metformin or thiazolidiediones.
Thus far, no drug interactions have been observed with the DPP-4 inhibitors. However,
recently post-marketing reports of anaphylaxis, angioedema, and rashes, including
Stevens-Johnson syndrome, have emerged in sitagliptin treated patients. [22] The reported
numbers of hypoglycemic events have been very low, as should be expected from the glucose-
induced GLP-1 secretion/effect.
Sitagliptin has been shown to reduce HBA1C by 0.8%-1.1% , to decrease fasting plasma glucose
and to increase beta cell function indices in type 2 diabetes patients, as a single therapy
or in combination with metformin or thizolidinediones, as compared to placebo [23-27].
Sitagliptin and glipizide have similar effect on plasma glucose when administered in
combination with metformin therapy. [28]
Arterial stiffness and endothelial dysfunction Augmentation of arterial blood pressure,
reflecting the pulsatile component of blood pressure and thus arterial stiffness, is a
well-known risk factor for cardiovascular disease outcome.[29-33] Augmentation index (AIx)
measurement, a non-invasive way of appreciating the rate of arterial stiffness, has been
shown to predict coronary artery disease (CAD) in whole population as well as in patients
with type 2 diabetes [32, 34, 35]. Differential effects of the drugs on arterial stiffness
may be, in part, responsible for the diversity of impacts of various antihypertensive
drug/treatments on CAD.[33] The Conduit Artery Function Evaluation (CAFE) study, a sub-study
to the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), examined the impact of two
different blood pressure lowering regimens, atenolol-thiazide based versus
amlodipine-perindopril based therapy, on derived central aortic pressure values and on
hemodynamics in 2199 patients.[33] Central pulse pressure was an independent risk factor for
composite outcome of total cardiovascular events/procedures and the development of renal
impairment. Similarly, statin drugs have been shown to exert additional beneficiary effects
on AIx, the result entirely independent of their primary, cholesterol lowering, effect.[36].
Regarding type 2 diabetes, it has been previously demonstrated that increase in adiponectin
levels, secondary to treatment with the insulin sensitizers pioglitazone or metformin, may
decrease arterial stiffness.[37] . By analogy, incretins, in addition to stimulatory effects
on insulin secretion, might have a positive impact on decreasing arterial stiffness in
diabetic patients. Nystrom et al. have demonstrated that GLP-1 improves endothelial
dysfunction in a small group of type 2 diabetes subjects with coronary heart disease [14].
However, the actual effect of DPP-4 on arterial stiffness has not yet been investigated.
According to the American diabetes association, treatment with biguanides should be started
in case of diagnosis of type 2 diabetes .If the targeted glycemia level is not achieved,
another medication should be added. In this respect, one cannot overemphasize the importance
of discovering positive additional effects, if any, of the administered antidiabetic drugs
on blood pressure, arterial stiffness, and oxidative stress and/or inflammation markers. The
purpose of the proposed clinical trial is to compare the effects of two different types of
insulin inducers, sulfonyl urea and incretin, on blood pressure, monitored within a 24h
period, as well as on arterial stiffness parameters. In addition, assessment of blood
markers for oxidative stress, as represented by 8-STAT-Isoprostane, oxidized LDL and [H202?
carbonil groups?], as well as of markers for inflammation, as represented by TGF-ß, Il-1,
Il-6, Il-4, Il-10 and highly sensitive CRP will be performed .
Methods The study has been designed as a prospective, randomized, single blind, cross-over
trial. It will include 60 diabetic patients, aged 18 years or older, treated with metformin.
Only patients with HbA1C levels within the range 7% - 11% will be enrolled in the study. All
patients will submit written informed consent to participate in the experiment prior to
their inclusion in the study.
The exclusion criteria will be as follows:
- CCT<30
- A history of treatment with incretins or sulfonylurea during the last 3 months
- Treatment with nitrates
- Uncontrolled heart failure
- Uncontrolled hypertension and/or any change in the hypertensive medications within one
month prior starting the study
- No proven regular treatment with aspirin or statins within one month prior starting the
study
- Any malignancy with life expectancy of less then 1 year
- pregnancy
Patients included in the study will be randomly assigned to one of the two experimental
groups: Group A: to receive sitagliptin, 100 mg by a single dose daily, Group B:
glibenclamide, 5 mg by a single dose daily. The latter dosage might be increased, if needed,
to 5 mg twice a day. After 3 month, a one-week wash-out period during which no antidiabetic
drugs (excluding metformin) will be administered, will be imposed on all patients .Following
1 week, a cross-over protocol will be applied: group A, earlier treated with sitagliptin,
will now receive glibenclamid and, vice versa, group B will start the sitagliptin treatment.
The primary end results aimed to be obtained from this study are detection of arterial
stiffness, defined as change in augmentation index measured by means of a non-invasive
technique using the commercially available SphygmoCor System, and the results of the 24 hour
blood pressure monitoring. The secondary end results would be oxidative stress parameters,
as evaluated by oxidized LDL and Isoprostanes, and markers of inflammatory status, including
measurements of pro-inflammatory interleukins and performance of highly sensitive CRP test.
All the patients enrolled in the study will be invited to the Research & Development Unit of
Assaf-Harofeh for three visits: prior to starting the experiment, following 3 months and
following 6 months. Their weight and abdominal circumference will be recorded; arterial
stiffness will be measured; then, they will be connected to a blood pressure halter,
recording their blood pressure for 24h. At each visit, 10ml periohera blood will be drawn
for evaluation of HBA1C, complete blood count, serum electrolytes, albumin, blood lipids,
fasting glucose 8F-STAT-Isoprostanes, oxidized LDL, nitric oxide, inflammatory interleukins
and highly sensitive CRP (hsCRP). Any side effects of the drugs and any complaint on the
event of hypoglycemia will also be recorded.
