July 6, 2005

Takeda Pharmaceutical Company Limited

Candesartan therapy can reduce the risk of diabetes in heart failure patients¹¹
Candesartan is the first angiotensin receptor blocker (ARB) shown to reduce the risk of diabetes in heart failure patients compared to placebo, in new study analysis¹

July 6, 2005, Osaka, Japan --- A reduction in the risk of developing diabetes has been shown in heart failure patients on candesartan cilexetil ("candesartan") therapy. New data from placebo controlled studies published yesterday in Circulation has shown a reduction in new onset of diabetes mellitus in candesartan treated patients across varying degrees of heart failure severity, body mass index (BMI), and in those on concomitant heart failure treatments.¹

Six per cent of patients in the candesartan group were newly diagnosed with diabetes during the study period (median 3.1 year), compared to 7.4% in the placebo group (p=0.020). The composite endpoint of new diabetes diagnosis or death occurred in 25.2% of patients in the active treatment group, compared to 28.6% in the placebo group (p=0.004). Consistent reduction rates of new onset of diabetes were observed in patient groups across varying severities of heart failure symptoms, and with concomitant drugs such as beta-blockers or diuretics for the treatment of heart failure. This effect was consistently observed in all subgroups examined with no evidence of heterogeneity among the 3 component trials in the CHARM Programme (Candesartan in Heart Failure - Assessment of Reduction in Mortality and Morbidity), although it appears that the magnitude of the effect may have been smaller in those receiving concomitant ACE inhibitors. In patients without concomitant ACE inhibitor therapy, a relative risk reduction in new-onset diabetes of approximately 29% by Candesartan was seen across the entire CHARM programme.

Lead investigator Professor Salim Yusuf, McMaster University, Hamilton, Canada, commented on this new data: "This finding that candesartan may prevent the develop-ment of diabetes in some patients could have important future implications for the treatment of certain patient populations, such as those with hypertension, previous myocardial infarction and heart failure, in whom such treatments have already been shown to reduce major vascular events."

Incidence of both diabetes and chronic heart failure is increasing, and treatments with the potential to prevent both conditions could have important clinical benefits. CHARM investigators prospectively specified a secondary analysis comparing Candesartan to placebo to assess prevention of diabetes in a broad range of heart failure patients.  Pre-specified outcomes for this analysis were the development of diabetes mellitus alone, or as a composite with all-cause mortality.

5,436 of the 7,601 patients in the overall CHARM population were not known to have diabetes at baseline. These patients (2,715 on Candesartan) were included in this new analysis. Patients were followed up at 2, 4, and 6 weeks, 6 months and then every 4 months until study end (median follow-up 3.1 years).

These results are consistent with those from previous trials which have indicated that ACE inhibitors or ARBs may reduce diabetes onset^{2,3,4,5,6,7,8,} though CHARM is the only study to date to provide evidence of the effect of an ARB in preventing diabetes in heart failure patients, compared to placebo.

In November 2004, Candesartan, already a well-established antihypertensive therapy, was granted EU* Marketing Authorisation for the treatment of patients with heart failure and left ventricular systolic dysfunction. In February 2005 the US Food and Drug Administration (FDA) approved Candesartan for the treatment of heart failure
(New York Heart Association Class II-IV and ejection fraction less than or equal to 40 percent). On 19 May 2005 the FDA also approved Candesartan for use on top of ACE-inhibitors in the treatment of heart failure.

These approvals of a CHF indication for Candesartan are based on the positive results of the CHARM clinical trial Programme. The results from CHARM identified Candesartan as the first ARB to reduce both death and heart failure hospital admissions in chronic heart failure patients with left ventricular systolic dysfunction, irrespective of background therapy.⁹

-- ENDS --

Notes to editors

• • CHARM study was sponsored and conducted by AstraZeneca.
• • *The MRP on this occasion covered all EU countries apart from France. The reference member state during this procedure was the UK. (* EU countries excluding France and prior to 2004 expansion. Belgium, Denmark, Germany, Greece, Spain, Ireland, Italy, Luxembourg, Netherlands, Austria, Portugal, Finland, Sweden, United Kingdom).
• • Candesartan cilexetil was discovered and originally synthesized by Takeda Pharma-ceutical Company Limited and it was jointly developed with AstraZeneca.
• • Candesartan cilexetil is marketed by Takeda as Blopress®, Amias® and Kenzen®, and by AstraZeneca as Atacand® under the license from Takeda Pharmaceutical Company Limited.

References

• 1. Yusuf S, Östergren J, Gerstein H, et al. Effects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation 2005; 112(26):48-53
• 2. Yusuf S, Gerstein H, Hoogwerf B et al. for the HOPE Investigators. Ramipril and the development of diabetes. JAMA. 2001; 286(15):1882-5.
• 3. Vermes E, Ducharme A, Bourassa MG et al. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003; 107(9):1291-6
• 4. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U et al for the LIFE study group. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003.
• 5. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288(23):2981-97.
• 6. Lithell H, Hansson L, Skoog I et al for the SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003; 21(5): 875-86.
• 7. Lindholm LH, Persson M, Alaupovic P et al. Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study). J Hypertens 2003; 21(8):1563-74.
• 8. Julius S, Kjeldsen SE, Weber M et al for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomsed trial. Lancet 2004; 363: 2022-31.
• 9. Young JB, Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic function. Results from the CHARM low-left ventricular ejection fraction trials. Circulation 2004;110:2618-26.

About CHARM

The CHARM Programme, which recruited 7,601 patients, was conducted in heart failure with an AT1-receptor blocker. Patients with classic symptomatic chronic heart failure − depressed left ventricular (LV) systolic function (Left Ventricular Ejection Fraction (LVEF) < 40%), were randomized into one of two studies − either an ACE-inhibitor intolerant population (CHARM-Alternative), or the population treated with ACE-inhibitors (CHARM-Added). In addition, patients with preserved LV systolic function (LVEF> 40%) were also randomized into a third study (CHARM-Preserved). All patients received either candesartan cilexetil or placebo.

About Takeda

Takeda, located in Osaka, Japan, is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to striving toward better health for individuals and progress in medicine by developing superior pharmaceutical products.

# # #