A secondary analysis of the Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity ( CHARM ) program evaluating the effects of the angiotensin II receptor blocker ( ARB ), Candesartan cilexetil ( Atacand ), in reducing the risk of development of diabetes in patients with heart failure and no previous diagnosis of diabetes, showed that Candesartan appears to prevent diabetes in heart failure patients, suggesting that the renin-angiotensin axis is implicated in glucose regulation.

In the overall CHARM program, 163 patients receiving Candesartan and 202 patients receiving placebo developed a new diagnosis of diabetes, for a relative risk reduction on Candesartan of 22% ( hazard ratio 0.78; p=0.020 ).

Atacand is indicated for the treatment of hypertension and heart failure ( NYHA class II-IV, LVEF less than or equal to 40% ), and is not indicated for the prevention of new onset diabetes.

The CHARM program consists of 3 parallel, randomized, placebo-controlled, double-blind trials in 7,599 symptomatic heart failure patients.
CHARM-Added ( n=2548 ) and CHARM-Alternative ( n=2028 ) enrolled patients with left-ventricular ejection fraction ( LVEF ) less than or equal to 40%, and CHARM-Preserved ( n=3023 ) enrolled patients with LVEF > 40%.
Patients were randomized to either Candesartan or matching placebo initiated at 4 mg or 8 mg and titrated as tolerated to 32 mg once daily.
Patients were followed for a minimum of 2 years, with median follow-up of 37.7 months.
The primary end point of each trial was cardiovascular death or heart failure hospitalization.

The CHARM program included 5,436 patients who did not have a diagnosis of diabetes at randomization.
The pre-specified analysis of new diagnosis of diabetes found that 163 ( 6.0% ) individuals in the group receiving Candesartan developed diabetes, compared with 202 ( 7.4% ) in the placebo group ( relative risk reduction 22%, hazard ratio 0.78; p=0.020 ).
The composite end point of death or new diagnosis of diabetes occurred in 25.2 percent of patients receiving Candesartan and 28.6 percent of patients in the placebo group, giving a relative risk reduction of 14% ( hazard ratio 0.86; p=0.004 ).

In February 2005, the US Food and Drug Administration ( FDA ) approved Atacand for the treatment of heart failure ( New York Heart Association Class II-IV and ejection fraction less than or equal to 40 percent ) to reduce the risk of death from cardiovascular causes and reduce hospitalization for heart failure.
In May 2005, the FDA approved the current label: "Atacand is indicated for the treatment of heart failure ( NYHA class II-IV ) in patients with left-ventricular systolic dysfunction ( ejection fraction less than or equal to 40% ) to reduce cardiovascular death and to reduce heart failure hospitalizations. Atacand also has an added effect on these outcomes when used with an ACE inhibitor."
The approvals were based on positive results of the CHARM-Alternative and CHARM-Added trials. In these patients with heart failure, Candesartan is the only ARB proven to reduce both cardiovascular death and heart failure hospitalizations and to provide these benefits with or without an ACE inhibitor. Candesartan is the only ARB with these proven benefits when used with conventional therapy that includes both an ACE inhibitor plus a beta-blocker.

In heart failure patients receiving Candesartan, hypotension, increases in serum creatinine, and hyperkalemia have occurred.
Caution should be observed for hypotension when initiating therapy.
Evaluation of patients with heart failure should always include assessment of renal function and volume status. Monitoring of blood pressure, serum creatinine, and serum potassium is recommended during dose escalation and periodically thereafter.
During concomitant use of Candesartan and lithium, careful monitoring of serum lithium levels is recommended.

The adverse event profile of Candesartan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients.
In the CHARM program, comparing Candesartan in total daily doses up to 32 mg once daily ( n=3803 ) with placebo ( n=3796 ), 21.0% of patients discontinued Candesartan for adverse events vs. 16.1% of placebo patients.

Source:

1) Circulation, 2005

2) AstraZeneca, 2005


XagenaMedicine2005