Telmisartan Versus Losartan in Kidney Transplantation
Condition: Renal Transplant
Study type: Interventional
Phase: Phase 2

Summary: 
      In renal transplant recipients, residual renal insufficiency combined to the effects of
      immunosuppressive therapy with steroids or calcineurin inhibitors may reduce insulin activity
      and may contribute to several of the abnormalities associated with the metabolic syndrome,
      such as hypertension, glucose intolerance and hyperlipidemia. In turn, insulin resistance,
      hypertension, hyperglycemia and dyslipidemia may importantly contribute to the excess
      cardiovascular risk of renal transplant patients (an excess comparable to that of diabetes
      subjects with over diabetic nephropathy)and may also accelerate progressive renal function
      deterioration and promote graft loss. Thus, amelioration of the insulin activity and of the
      related metabolic syndrome is a key component of treatments aimed to improve patient and
      graft survival in renal transplant recipients. Recently, drugs such as peroxisome
      proliferators-activated receptor-gamma activators, that ameliorate insulin sensitivity and
      metabolic syndrome, have become available.These agents, however, can provoke fluid retention,
      weight gain, edema and, in some cases, heart failure.

      Recent studies showed that telmisartan, an angiotensin II type 1 receptor antagonist, in
      addition to block the angiotensin II type 1 - a key surface receptor involved in the
      regulation of blood pressure - may also activate peroxisome proliferators-activated
      receptor-gamma activators, thus improving some of the features of the metabolic syndrome.
      Thus telmisartan may substantially reduce the overall cardiovascular and renal risk of renal
      transplant recipients by ameliorating some of the modifiable components of the metabolic
      syndrome. On the other hand, telmisartan is devoid of the adverse effects of peroxisome
      proliferators-activated receptor-gamma activators such as fluid retention, and has therefore
      a remarkably better risk/benefit profile. Thus, whether telmisartan in addition to the
      beneficial effects of a reference angiotensin II type 1 receptor antagonist (such as
      losartan) may offer adjunctive advantages related to improved insulin sensitivity in renal
      transplant patients on chronic therapy with steroids and/or calcineurin inhibitors, is worth
      investigating.
    

Detailed description: 
      BACKGROUND In renal transplant recipients, residual renal insufficiency combined to the
      effects of immunosuppressive therapy with steroids or calcineurin inhibitors may reduce
      insulin activity and may contribute to several of the abnormalities associated with the
      metabolic syndrome, such as hypertension, glucose intolerance and hyperlipidemia. In turn,
      insulin resistance, hypertension, hyperglycemia and dyslipidemia may importantly contribute
      to the excess cardiovascular risk of renal transplant patients (an excess comparable to that
      of diabetes subjects with over diabetic nephropathy)and may also accelerate progressive renal
      function deterioration and promote graft loss. Thus, amelioration of the insulin activity and
      of the related metabolic syndrome is a key component of treatments aimed to improve patient
      and graft survival in renal transplant recipients. Recently, drugs such as peroxisome
      proliferators-activated receptor-gamma activators, that ameliorate insulin sensitivity and
      metabolic syndrome, have become available. These agents, however, can provoke fluid
      retention, weight gain, edema and, in some cases, heart failure. Thus, the risk/benefit
      profile of peroxisome proliferators-activated receptor-gamma activators is still uncertain,
      in particular in renal transplant patients where the risks of therapy may overwhelm the
      potential benefits.

      Recent studies showed that telmisartan, an angiotensin II type 1 receptor antagonist, in
      addition to block the angiotensin II type 1 - a key surface receptor involved in the
      regulation of blood pressure - may also activate PPAR-gamma, thus improving some of the
      features of the metabolic syndrome, such as hyperglycemia and dyslipidemia in people with
      hypertension and/or diabetes. Thus, in addition to control high blood pressure and to limit
      some of the adverse effects of angiotensin II, including target organ damage, graft fibrosis
      and cyclosporine (CsA) nephrotoxicity, telmisartan may also substantially reduce the overall
      cardiovascular and renal risk of renal transplant recipients by ameliorating some of the
      modifiable components of the metabolic syndrome, such as hypertension, glucose intolerance
      and hyperlipidemia. On the other hand, telmisartan is devoid of the adverse effects of
      peroxisome proliferators-activated receptor-gamma activators such as fluid retention, and has
      therefore a remarkably better risk/benefit profile. Thus, whether telmisartan in addition to
      the beneficial effects of a reference AII receptor antagonist (such as losartan) may offer
      adjunctive advantages related to improved insulin sensitivity in renal transplant patients on
      chronic therapy with steroids and/or calcineurin inhibitors, is worth investigating.

      AIMS The primary aim is to compare the short-term effects of telmisartan and losartan on
      insulin sensitivity in kidney transplant recipients with stable renal function and
      concomitant treatment with steroids and/or calcineurin inhibitors.

      DESIGN This will be a pilot, explorative study. On the basis of previous experimental
      evidence, a crossover study on 20 patients should have the power to detect a statistically
      significant difference in the effect on insulin activity between each treatment period as
      compared to baseline.

      Patients will be randomised on a 1:1 basis to the sequence Telmisartan-Losartan or to
      sequence losartan-telmisartan.
    

Intervention name(s): Telmisartan; Losartan
Intervention type(s): Drug; Drug
Intervention description(s): One week 40 mg daily, followed by fifteen weeks treatment period with 80 mg daily.; One week 50 mg daily, followed by fifteen weeks treatment period with 100 mg daily.
Intervention MeSH terms: Losartan; Telmisartan
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Telmisartan; Losartan; Renal transplant