A new analysis of data from the landmark Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA) published in Diabetes Care has identified the major predictors of new-onset diabetes (NOD) in patients with hypertension(1).
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.
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: amlodipine and the ACE inhibitor perindopril (Coversyl) with β-blocker/diuretic combination (atenolol ± thiazide). 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.
ASCOT-BPLA Study Design
A total of 19,257 patients were randomly assigned to receive one of the two antihypertensive regimens (amlodipine +/- perindopril or atenolol +/- thiazide). Among them, 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.
Patients 34% less likely to develop NOD with the amlodipine /Coversyl combination
Results showed that the use of atenolol with or without a diuretic were among the major predictors of NOD in these patients. Hypertensive patients allocated to amlodipine and perindopril were found 34% less likely to develop NOD compared with those allocated to the β-blocker/diuretic combination. 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 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.
Other determinants of New Onset Diabetes
The new analyses also showed that other major predictors of NOD in patients with hypertension were baseline fasting plasma glucose (FPG) level greater than 5mmol/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 5mmol/L. The model developed from these data will allow clinicians to accurately predict NOD among hypertensive patients.
Conclusion
“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 new onset diabetes,” states Dr Ajay Gupta, lead author and Research Fellow at the International Centre for Circulatory Health, Heart & Lung Institute, Imperial College, London. “Unfortunately, -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 β-blocker and diuretic combinations could be avoided.”
More generally, a recent metanalysis of 22 clinical trials found 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 -blockers and diuretics having a diabetogenic effect.
All other renin-angiotensin-aldosterone system inhibitors have however not always shown the same benefits on NOD as perindopril. Evidence did not demonstrate a significantly protective effect of ramipril against NOD (DREAM trial) and an ACEI/CCB antihypertensive regimen was found superior to an ARB/thiazide diuretic in reducing the risk of NOD (STAR trial).
ASCOT is the 5th positive morbidity-mortality trial with perindorpil alone or in association, making Coversyl the ACE inhibitor, and the antihypertensive, with most evidence-based data.
1-Gupta AK, Dahlof B, Dobson J, Sever P, Wedel H, Poulter N. Diabetes Care. 2008 May;31(5):982-8.
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