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A new analysis of data from the landmark Anglo-Scandinavian
Cardiac Outcomes Trial - Blood Pressure Lowering Arm (ASCOT-BPLA) published
today in Diabetes Care has identified the major predictors of new-onset
diabetes (NOD) in patients with hypertension. In particular, the data show
that hypertensive patients allocated to amlodipine and the ACE inhibitor
perindopril (Coversyl(R), Servier) were 34% (HR 0.64 95% CI 0.59 to 0.74)
less likely to develop NOD compared with those allocated to a
beta-blocker/diuretic combination (atenolol plus or minus thiazide).(1)
For the investigators, given the evidence from ASCOT-BPLA and
previous trials, it seems that the beneficial effect of the
amlodipine/perindopril regimen is largely a composition of the protective
effect of Coversyl, amlodipine playing a neutral role, whereas atenolol and
thiazide have adverse effects. The benefits of perindopril on NOD have not
always been seen with all other RAAS inhibitors: - the recent analyses of the
DREAM trial did not show a significantly protective effect of ramipril
against NOD(2). More recently, in the STAR trial(3), an ACEI/CCB
antihypertensive regimen was superior to an ARB/thiazide diuretic in reducing
the risk of NOD.
"This new ASCOT-BPLA analyses provide robust evidence that
treating hypertensive patients with a regimen based on amlodipine and
perindopril in comparison to atenolol and thiazide significantly reduces the
risk of NOD," states Dr Ajay Gupta, lead author and Research Fellow at the
International Centre for Circulatory Health, Heart & Lung Institute, Imperial
College, London. "Unfortunately, beta-blockers and diuretics, often in
combination, are used extensively worldwide. If we translate our findings
into patient numbers in the US for example, 250 000 cases of NOD each year
related to the use of beta-blocker and diuretic combinations could be avoided.
It therefore seems at best unwise to use these drugs in preference to others
such as a calcium channel blocker plus an ACE inhibitor, particularly since
the latter combination has been shown to be more cost-effective."
Other determinants of NOD
The new analyses also showed that other major predictors of
NOD in patients with hypertension were baseline fasting plasma glucose (FPG)
level greater than 5 mmol/L, body mass index (BMI), serum triglyceride and
systolic blood-pressure (SBP). FPG was the most powerful predictor, with risk
increasing nearly six times for each mmol/L rise above 5 mmol/L. The model
developed from these data will allow clinicians to accurately predict NOD
among hypertensive patients.(1)
Hypertension and type 2 diabetes
Observational data suggest that hypertension is a risk factor
for type 2 diabetes, and hence the two conditions frequently coexist. This
risk is variably affected by different classes of antihypertensive
medication. A recent metanalysis of 22 clinical trials suggests that the
association between antihypertensive agents and incident diabetes is lowest
for ACE inhibitors and angiotensinogen-receptor blockers, followed by calcium
channel blockers and placebo, with beta-blockers and diuretics having a
diabetogenic effect.(4)
ASCOT-BPLA
ASCOT-BPLA was a major multinational trial involving over
19,000 hypertensive patients that compared the effectiveness of two different
treatment strategies at reducing cardiovascular events. The newer treatment
strategy (amlodipine and perindopril) offered such significant advantages
over the older treatment strategy (atenolol and bendroflumethiazide) that the
trial was stopped early by the Data Safety Monitoring Board in December 2004.
The aim of the new analysis of ASCOT-BPLA data was to
determine the baseline predictors of NOD in a large population of patients
with hypertension and to develop a risk score to detect those at high risk
for NOD. Of 19,257 randomized patients in the study, 14,120 were considered
"at risk" of developing diabetes at baseline, and 1,366 (9.7%) subsequently
developed NOD during follow-up (median duration, 5.5 years). Independent
predictors of NOD were developed with a multivariate Cox model, and these
predictors were used to calculate individual risk scores.
"Baseline FPG greater than 5mmol/l, BMI and the use of
atenolol with or without a diuretic were among the major predictors of NOD in
these patients," points out Dr Gupta. "The model we developed from the
ASCOT-BPLA data will allow accurate prediction of NOD among hypertensive
subjects."
Coversyl
Coversyl, discovered and developed by Servier, is licensed
worldwide for the treatment of hypertension and heart failure. Coversyl is
also indicated for use in stable coronary artery disease to reduce the risk
of cardiac events in patients with a history of MI and/or revascularization.
ASCOT is the 5th positive morbidity-mortality trial with
perindorpil alone or in association, making Coversyl the ACEI, and the
antihypertensive, with most evidence-based data. Perindopril is marketed in
118 countries under the trade names COVERSYL(R), COVEREX(R), ACERTIL (R),
PRESTARIUM(R), PREXANIL(R), PREXUM(R), COVERENE(R), COVERSUM (R),
PROCAPTAN(R), ARMIX(R) .
ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) involved
over 19,000 hypertensive patients from the UK, Ireland, and Scandinavia and
was endorsed by the Buy synthroid without prescription British Hypertension Society. All the patients had
hypertension and at least three prespecified cardiovascular risk factors such
as being over 55 years old, being a smoker, and having a family history of
coronary events. The aim of the ASCOT trial was to test the hypothesis that a
newer antihypertensive regimen is more effective than an older regimen in the
primary prevention of coronary heart disease. The average length of treatment
was about 5 1/2 years.
The early cessation of the study because of the clear health
benefits in favor of the amlodipineplus or minusperindopril combination meant
that there was not enough statistical power for the primary end point
(nonfatal MI + fatal CHD) to reach statistical significance, although there
was a trend towards a 10% reduction in favor of the amlodipine plus or
minus perindopril strategy. Significant secondary end points included
all-cause mortality, cardiovascular mortality, fatal and nonfatal stroke, and
total cardiovascular events and procedures. New-onset diabetes was a tertiary
end point.
References
(1) Gupta AK, Dahlof B, Dobson J, Sever P, Wedel H, Poulter N.
Determinants of new-onset diabetes among 19,257 hypertensive patients
randomised in the ASCOT-BPLA trial and the relative influence of
hypertensive medication. Diabetes Care. 2008 Feb 11
(2) The DREAM Trial Investigators. Effect of ramipril on the
incidence of diabetes 10.1056/NEJMoa065061. N Engl J Med.
2006;355:1551-1562
(3) The STAR Trial Investigators. Differences in glucose tolerance
between fixed-dose antihypertensive drug combinations in people with
metabolic syndrome. Diabetes Care. 2006;29:2592 - 2597.
(4) Elliott WJ, Meyer PM. Incident diabetes in clinical trials of
antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:201-207.

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