Association Between Rosiglitazone Use and Clinical Course of Diabetic Nephropathy: Population-Based Study
Association Between Rosiglitazone Use and Clinical Course of Diabetic Nephropathy: Population-Based Study
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.
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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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