New analysis of a landmark study data Identifies major predictors of new-onset diabetes (NOD) among hypertensives. 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). A new analysis of data from the landmark Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA) 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), were 34% less likely to develop NOD compared with those allocated to a beta-blocker/diuretic combination (atenolol plus or minus thiazide).
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 the ARB, 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. 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 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."
The new analyses also showed that other major predictors of NOD in patients with hypertension were baseline fasting plasma glucose (FPG) level greater than 90mg/Dl. (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.
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.
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 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, 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) ..
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.
Diabetes Care, May 2008