• Effect of Cinacalcet on Cardiovascular Disease
in Patients Undergoing Dialysis
• Dr. Glenn M. Chertow et al N Engl J Med
• Disorders of mineral metabolism- extraskeletal
(including vascular) calcification among patients with
chronic kidney disease.
• It has been hypothesized that treatment with the
calcimimetic agent cinacalcet might reduce the risk
of death or nonfatal cardiovascular events in such
Rationale behind the trial
1. Various biochemical abnormalities in sHPT are
associated with increased mortality.
2. Cinacalcet decreases the levels of PTH,P and Ca X P
which are associated with increased mortality.
Calcimimetics : Definition
• Calcimimetic agents are small organic molecules that
act as allostersic activators of the calcium sensing
receptors (CaSR) in the parathyroid gland and other
• Calcimimetics increase the threshold sensitivity of the
CaSR to extracellular calcium leading to activation of
the CaSR at lower than normal levels of serum calcium.
• As a result, in the presence of these agents, even the
low levels of ionized calcium typically present in
patients with chronic kidney disease exert a
suppressive effect on PTH secretion
Molecular targets regulating parathyroid gland function include, in rank
order of importance, CASR, VDR, and a hypothetical phosphate sensing
• CASR is the major regulator of PTH transcription, secretion,
and parathyroid gland hyperplasia.
• VDR, which affects PTH transcription but not PTH secretion,
may have a subordinate physiologic role to calcium in
regulating parathyroid gland function.
• Secondary hyperparathyroidism and bone abnormalities in
VDR-deficient mice can be corrected by normalizing serum
calcium concentrations, whereas
• Hyperparathyroidism in CASR-deficient mice cannot be
corrected by elevated 1,25(OH)2D3.
• Multicenter, prospective, randomized, placebo-
• Compared cinacalcet with placebo in 3883 adults
• All the patients were eligible to receive conventional
therapy, including phosphate binders, vitamin D
sterols, or both.
• Randomization was stratified according to country
and diabetes status with the use of fixed blocks.
• The sponsor, investigators, and patients were
unaware of the treatment assignments
• Patients received either cinacalcet or placebo at a
starting dose of 30 mg daily.
• Patients were eligible for dose escalation once every
4 weeks during a 20-week escalation phase (to 60
mg, 90 mg, 120 mg, or 180 mg daily) or every 8
weeks during follow-up, depending on levels of
plasma parathyroid hormone and serum calcium.
Study End Points
• The primary composite end point was the time to
death or the first nonfatal cardiovascular event
(myocardial infarction, hospitalization for
unstable angina, heart failure, or a peripheral
• Secondary end points included the time to the
individual components of the primary composite
end point, death from cardiovascular causes,
stroke, bone fracture, and parathyroidectomy.