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New-Onset Diabetes -- New Analysis of the Blood Pressure-Lowering Arm of ASCOT
DisclosuresLinda Brookes, MSc
Presenter: Ajay K Gupta, MD, MSc (International Centre for Circulatory Health NHLI, Imperial College, London, United Kingdom)
The latest analysis of the results from the blood pressure lowering-arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA) has shown that a regimen based on a calcium channel blocker (CCB) (amlodipine), with or without addition of an angiotensin converting enzyme (ACE) inhibitor (perindopril), reduced the risk of new-onset diabetes by 34% in hypertensive patients, compared with a regimen based on a beta-blocker (atenolol) with or without a thiazide-type diuretic, bendroflumethiazide.[1]
The ASCOT investigators believe that this finding has implications for the future role of beta-blockers and diuretics in the management of patients with hypertension and suggest that physicians adopt what they refer to as "the ASCOT strategy, an evidence-based strategy for combining CCBs and ACE inhibitors," to get their patients to currently recommended target blood pressures. "By so doing, they know that they will reduce the risk of new-onset diabetes by almost one third," the investigators say. On the basis of the results of this most recent analysis, the ASCOT investigators have also developed a new risk score model that can be used to identify those hypertensive patients at highest risk of new-onset diabetes.
ASCOT-BPLA: Main Study
The multicenter, prospective, randomized, controlled ASCOT-BPLA study was designed to compare a newer, CCB-based antihypertensive regimen with the most commonly prescribed combination antihypertensive regimen at the time, a beta-blocker plus a thiazide diuretic, in a population of over 19,000 hypertensive adults at moderate risk of developing cardiovascular disease. ASCOT-BPLA was supported mainly by Pfizer (New York, NY), with additional funding by Servier Research Group (Paris, France).
Patients enrolled in ASCOT were aged 40 to 79 years, had hypertension (screening and baseline blood pressure ≥ 160/100 mm Hg untreated or ≥ 140/90 mm Hg treated with ≥ 1 drugs), no previous myocardial infarction (MI) or current coronary heart disease (CHD), and ≥ 3 other cardiovascular risk factors, such as male gender, age ≥ 55 years, smoking, or diabetes mellitus.[2] Diabetes at baseline was defined as:
Fasting plasma glucose (FPG) ≥ 7 mmol/L (126 mg/dL) and/or random glucose ≥ 11.1 mmol/L (200 mg/dL);
Self-reported diabetes and receiving dietary or drug therapy; or
Presence of both impaired fasting glucose (IFG) (≥ 6 mmol/L) and glucosuria in absence of the above 2 criteria.
Patients were assigned either to amlodipine 5 to 10 mg, adding perindopril 4 to 8 mg as required, or to atenolol 50 to 100 mg, adding bendroflumethiazide 1.25 to 2.5 mg and potassium as required (atenolol-based regimen). Blood pressure targets were < ci =" confidence" hdl =" high-density" hr =" hazard"> 5 mmol/L)†
5.80
5.34-6.43
BMI (per 5-unit increase)
1.49
1.38-1.62
Triglyceride (per mmol/L)
1.12
1.07-1.17
SBP (per 10 mm Hg)
1.07
1.04-1.10
Use of non-CAD medication (Y/N)
1.25
1.11-1.40
*For all comparisons, P < .001†Baseline risk = FPG ≤ 5 mmol/L. BMI >35 kg/m2 given similar risk; hazard ratio per 5-unit increase from baseline.BMI = body mass index; CI = confidence interval; FPG = fasting plasma glucose; HR = hazard ratio.
Dividing the patient population into quartiles based on these factors showed that risk of new-onset diabetes increased with risk score, the patients with the highest score (4th quartile) having an almost 20-fold higher risk than the patients in the lowest (1st) quartile (Table 3). Within each quartile, the patients taking the atenolol-based regimen were at higher risk than those on the amlodipine-based regimen. Comparison of the observed numbers of events with the expected probabilities of the development of diabetes predicted using the risk score showed no difference.
Table 3. New-Onset Diabetes According to Risk Quartiles

1st Quartile
2nd Quartile
3rd Quartile
4th Quartile
Hazard ratio
1
2.5
5.0
19.0
(95% CI)

(1.8-3.5)
(3.7-6.8)
(14.3-25.4)
CI = confidence interval; HR = hazard ratio
Dr. Gupta believes that this risk model "is robust, has an excellent discriminative ability, and could potentially play an important role in clinical practice." The designated discussant at the World Cardiology Congress, José L. Zamorano Gomez, MD, PhD (University Clinic San Carlo, Madrid, Spain), agreed that the risk score obtained by combining the most important risk factors for new-onset diabetes "makes it possible to calculate in advance a risk score which was extremely good at discriminating between risk groups presented in quartiles."
Implications for Treatment of Hypertension
Dr. Gomez also pointed out that, although the ASCOT analysis and other trials seem to indicate that amlodipine has a neutral effect with respect to development of new-onset diabetes, it is unlikely that the 34% difference in the 2 ASCOT treatment groups was entirely due to the ACE inhibitor in the "amlodipine plus or minus perindopril group," because not all patients in this group received perindopril. "Consequently, a certain proportion of the final effect must be due to the atenolol plus or minus diuretic group, particularly atenolol," he stated. Dr. Gomez believes that now that the risk of new-onset diabetes with these drugs has been demonstrated, preventing new-onset diabetes should be regarded in the same light as a "compelling indication" in hypertension management guidelines.
Commenting separately on the latest data, Neil Poulter, MD, MSc (Imperial College, London, UK), Secretary of the ASCOT Executive Committee, said: "These findings have critically important implications for many thousands of people. Hypertension already increases the risk of diabetes 2-3 times. Now we know that the commonly used combination of a beta-blocker plus or minus diuretic significantly increases the risk compared with a new combination, amlodipine plus or minus perindopril. Physicians should think carefully before using the beta-blocker-based strategy to treat hypertension."
The main results of ASCOT reported in 2005[3] prompted a review of guidelines for the management of hypertension in the United Kingdom by the National Institute for Health and Clinical Excellence (NICE), working with the British Hypertension Society. The resulting joint guideline, published in June 2006,[5] included the recommendation that beta-blockers should no longer be preferred initial therapy for hypertension, relegating them to fourth line. Although the greater risk of new-onset diabetes with beta-blockers was acknowledged, the guideline also pointed out that most clinical trials upon which the recommendation was based used atenolol, and other beta-blockers might not carry the same risk. The guideline retained diuretics as a first-line option in patients aged ≥ 55 years, although reports of ongoing discussions had indicated that diuretics would also be removed as recommended first-line drugs.
Commenting in Barcelona on the UK guideline, Peter S. Sever, MD, PhD (Imperial College, London), Co-chairman of the ASCOT Executive Committee, said, "We know from other trials, including Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT),[6] that diuretics are metabolically unfriendly, that they increase fasting plasma glucose, and they are not lipid friendly and there is no doubt that they do contribute to the diabetes." He stressed that "the evidence for not including a diuretic at least in your first and second choice and replacing it with a CCB and an ACE inhibitor is very strong. Why would you want to increase the risk, even if it is not as great as for a beta-blocker, if you have alternative therapies that are now available in generic formulations, so that there is no cost issue as there was before?"
Prof. Sever stressed the increased risk hypertensive patients face if they have diabetes. Regardless of the presence of other risk factors such as hypertension, dyslipidemia, or smoking, or how many risk factors are present, "in a patient with diabetes the overall risk is enhanced dramatically," he said. "A patient with hypertension and diabetes is at equivalent risk to a hypertensive patient who has already had an MI and is nondiabetic. We regard it as the equivalent to secondary prevention in patients with diabetes -- we have to assume they have got established cardiovascular disease," he added.
The ASCOT Strategy
Prof. Sever and his colleagues urge physicians to adopt "the ASCOT strategy," ie, combining CCBs and ACE inhibitors for treatment of hypertension, with the addition of a statin, based on evidence from the lipid-lowering arm of the ASCOT study (ASCOT-LLA), for which over 10,000 patients in the blood pressure lowering study also received atorvastatin 10 mg or placebo daily.[7] "We know from ASCOT-BPLA that this combination will reduce cardiovascular mortality and all-cause mortality, reduce the incidence of MI, and reduce stroke incidence compared with the more conventional and widely used beta-blocker/thiazide combination therapy," said Prof. Sever. "We also know from ASCOT-LLA that most hypertensives will benefit from addition of a statin. The risk reductions were greater than one third for MI and about one quarter for stroke."
Another crucial management strategy to get blood pressure to target is to get a fast, early reduction, according to Prof. Sever.
"We know, from unpublished data from ASCOT, that the early and rapid reductions in blood pressure were associated with dramatic reductions in event rates, MI, and stroke. So with good blood pressure control, the addition of lipid lowering with statins and the preference for the so-called 'newer strategy' of CCB and ACE inhibitors, with all that package -- the ASCOT strategy -- we can confidently say that in hypertensive patients we can reduce the incidence of MI and stroke by nearly two thirds. Out in the real world the majority of hypertensives are poorly controlled, often on inappropriate treatment, and the vast majority are not receiving statins. This is the sort of package that will deliver cardiovascular protection if it was adopted more widely in coronary care."
Although the overall ASCOT population was mainly (95%) white, Prof. Sever believes the strategy based on the ASCOT findings can be applied to other ethnic groups, including black and Asian patients. "These populations are at very real risk of developing new-onset diabetes and we see no reason why our results should not be applied to other ethnic groups," he said.
References
Gupta A. Determinants of new-onset diabetes among hypertensive patients randomised in the ASCOT-BPLA Trial. Presented at the World Congress of Cardiology 2006, September 2-6, 2006, Barcelona, Spain: Clinical trial update I, September 6, 2006.
Sever PS, Dahlöf B, Poulter NR, et al; ASCOT investigators. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. J Hypertens. 2001;19:1139-1147. Abstract
Dahlöf B, Sever PS, Poulter NR, for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet. 2005;366:895-906. Abstract
WHO. Department of Non-Communicable Disease Surveillance. WHO 1999 criteria for diagnosis of diabetes mellitus. Geneva: World Health Organization; 1999: 1-59.
NICE clinical guideline 34. Hypertension: management of hypertension in adults in primary care (partial update of NICE clinical guideline 18). London: National Institute for Health and Clinical Excellence; 2006. Available at www.nice.org.uk/CG018.
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative 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;288:1981-1997.
Sever PS, Dahlöf B, Poulter NR, et al; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial -- Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet. 2003;361:1149-1158. Abstract
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