Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT00497666 |
| Other study ID # |
346147Rosi |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
July 6, 2007 |
| Last updated |
July 6, 2007 |
| Start date |
August 2007 |
| Est. completion date |
December 2007 |
Study information
| Verified date |
July 2007 |
| Source |
Assaf-Harofeh Medical Center |
| Contact |
Leonid S Feldman |
| Phone |
+972-8-9779383 |
| Email |
leonidf[@]asaf.health.gov.il |
| Is FDA regulated |
No |
| Health authority |
Israel: Ministry of Health |
| Study type |
Observational
|
Clinical Trial Summary
Recent data show that Rosiglitazone treatment can reduce proteinuria in diabetic patients.
However, currently there are no trials that examine the effects of Rosiglitazone on kidney
disease progression, that is, doubling of serum creatinine or time to onset of end-stage
renal disease, in patients with diabetic nephropathy.
We decided to study retrospectively the possible association between rosiglitazone use and
clinical course of diabetic nephropathy, including rate of deterioration of renal function,
appearance and progression of microalbuminuria/proteinuria, survival and acceptance to renal
replacement therapy.
Description:
Background Type 2 diabetes mellitus is a public health concern, and projections of its
future effect are alarming. According to the World Health Organization, diabetes affects
more than 170 million people worldwide, and this number will rise to 370 million by 2030
[1]. About one third of those affected will eventually have progressive deterioration of
renal function [2, 3]. The first clinical sign of renal dysfunction in patients with
diabetes is generally microalbuminuria (a sign of endothelial dysfunction that is not
necessarily confined to the kidney)[4], which develops in 2 to 5 percent of patients per
year [5,6]. In type 2 diabetes, unlike type 1 diabetes [7], microalbuminuria is seldom
reversible [8], but, instead, progresses to overt proteinuria in 20 to 40 percent of
patients.[9,10]. In 10 to 50 percent of patients with proteinuria, chronic kidney disease
develops that ultimately requires dialysis or transplantation [11,12,13]. Forty to 50
percent of patients with type 2 diabetes who have microalbuminuria eventually die of
cardiovascular disease [14,15]; this is three times as high a rate of death from cardiac
causes as among patients who have diabetes but have no evidence of renal disease [6].
In patients with diabetes and renal disease, lowering blood pressure and the levels of
urinary albumin is effective in reducing the risk of end-stage renal disease as well as that
of myocardial infarction, heart failure, and stroke [16]. Angiotensin-converting–enzyme
(ACE) inhibitors or angiotensin II antagonists appear to be the most effective
renoprotective and antihypertensive agents [11, 12, 17-21] . Treatment with the ACE
inhibitor enalapril over a period of six years decreased the incidence of microalbuminuria
in patients with type 2 diabetes who were normotensive and not obese [22].
Preventing (or delaying) the development of microalbuminuria is a key treatment goal for
renoprotection [23] and, possibly, for cardioprotection [4]. Recent clinical trials
suggested that inhibition of the renin–angiotensin system may actually prevent nephropathy.
The post hoc analyses of the reduction in hypertension in the Heart Outcomes Prevention
Evaluation study [18] and in the Losartan Intervention for Endpoint study [24] found a lower
incidence of overt nephropathy in subjects with type 2 diabetes who received therapy that
inhibited the renin–angiotensin system than in controls.
Recent BENEDICT study indicates that treatment with trandolapril with or without verapamil
significantly reduces the incidence of microalbuminuria in patients with type 2 diabetes and
normal urinary albumin excretion, as compared with placebo [25]. Trandolapril alone also
appeared to decrease the incidence of microalbuminuria, whereas verapamil had no effect.
Thiseffect of trandolapril plus verapamil and trandolapril alone in preventing
microalbuminuria exceeded expectations based on changes in blood pressure alone.
Unfortunately, even with the appropriate use of available therapy, diabetic nephropathy
still remains the leading cause of ESRD [2]. More effective strategies are needed in order
to retard the progression of diabetic nephropathy and to reduce cardiovascular mortality in
diabetic population.
Thiazolidinediones (TZDs) represent a class of compounds currently used for the treatment of
type 2 DM that exert their hypoglycemic properties through reduction of IR [26]. These
agents act by stimulating a certain type of nuclear receptor, called peroxisome
proliferator-activated receptor gamma (PPAR ). Such receptors are abundant in adipose tissue
cells, but they are also present in various other cell types, such as vascular smooth muscle
cells, macrophages, vascular endothelial cells, colon epithelial cells, as well as renal
glomerular and tubular cells. Through transcriptional regulation of various genes, PPAR
receptors play an important role in adipocyte differentiation and lipid and carbohydrate
metabolism [26]. Apart from improving glycemic control in patients with type 2 DM, several
lines of evidence support the notion that TZDs have beneficial effects on other components
of the metabolic syndrome, such as blood pressure (BP) lowering, triglyceride reduction,
high-density lipoprotein–cholesterol elevation, redistribution of body fat away from the
central compartment, decrease of C-reactive protein and plasminogen activator inhibitor -1
(PAI-1) levels, and others [26].
Additionally, several animal studies demonstrate that TZDs also reduce urine albumin or
protein excretion and protect against injury to the kidney [27]. Moreover, experimental
studies exposed numerous actions of TZDs in the kidney that could explain a possible
renoprotective effect [27-30]. Our recent study on diabetic rats showed that rosiglitazone
exerts its anti-inflammatory renoprotective effect by inhibition of mesangial cells
proliferation, downregulation of apoptosis and blunting responsiveness to angiotensin-2
[31].
Human study also report significant reductions in UAE among patients with type 2 diabetes by
rosiglitazone [32].
Another human study was part of a cardiac safety study where rosiglitazone 4 mg b.i.d. was
compared to glyburide in 121 patients for 52 weeks [32]. After 28 weeks of treatment, both
groups had significant reductions in ACR of about 30%, but after 52 weeks only rosiglitazone
group continued to demonstrate a significant ACR reduction. This finding suggests that
duration of follow-up is an important variable in assessing the effect of TZDs [32].
Overall, the above data clearly show that TZD treatment can reduce UAE. However, it should
be emphasized that currently there are no trials that examine the effects of TZDs on kidney
disease progression, that is, doubling of serum creatinine or time to onset of end-stage
renal disease, in patients with diabetic nephropathy [33]. Such studies are needed in order
to provide the best evidence for a renoprotective effect of TZDs.
Based on this data, we decided to study the possible association between rosiglitazone use
and clinical course of diabetic nephropathy, including rate of deterioration of renal
function, appearance and progression of microalbuminuria/proteinuria, survival and
acceptance to renal replacement therapy.
Methods. Study population. The study is planned as retrospective cohort study using
automated clinical data of Central Region Clalit Health Survices from 1999 until 2007.
Inclusion criteria: 1. Diagnosis of Diabetes Mellitus Type II; 2. Treatment With Oral
hypoglycemics; 3. Availability of Baseline and follow up clinical data Exclusion criteria:
1. Insulin Therapy at baseline; 2. Malignancy Patients will be divided into 2 groups:
rosiglitazone-treated group and non-treated with rosiglitazone ( control) group.
Baseline Data ( separately for two groups). Number of patients. Gender Race/etnicity Age
Weight, BMI Duration of DM Diabetic microangiopathy: retinopathy, neuropathy, nephropathy
Medications for DM Creatinine Microalbumin Proteinuria HbA1c% Hb Ca, P, PTH Albumin
Hypertension: BP Cholesterol, LDL, TG Smoking: current, previous Alcohol consumption
Comorbidites: HTN, CAD, CHF, PVD, Hypercholesterolemia, CVA/TIA Drugs: ACEi, ARBs, CCB,
beta-blockers, statines, antiplatlate Use of nephrotoxic medications: NSAIDs
Follow up data Duration of rosiglitasone therapy/follow up Use of contrast media during
study
Every year data:
Creatinine eGFR Microalbumin Proteinuria HbA1C% Start of insulin therapy
Events:
Hospitalisation (cause) Death (cause) ESRD/Dialysis Reported CHF MI CVA Angiography PVD
Amputation References
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