Chicago, IL - Investigators in the large Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) report that in that trial, there was "no evidence of superiority" of the calcium-channel blocker amlodipine or the ACE inhibitor lisinopril over the diuretic chlorthalidone as a first step in antihypertensive therapy, regardless of whether patients were normoglycemic or had impaired fasting glucose (IFG) or frank diabetes mellitus (DM) [1].

In a separate report, an overview of 27 randomized clinical trials carried out by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) showed "little difference" between ACE inhibitors, calcium-channel blockers, angiotensin receptor blockers (ARBs), or diuretics/beta blockers in short- and medium-term cardiovascular outcomes for hypertensive patients with or without diabetes, the authors conclude [2].

The reports are published in the June 27, 2005 issue of the Archives of Internal Medicine.

ALLHAT, previously published [3] and much discussed, compared CV outcomes with lisinopril and amlodipine vs chlorthalidone in hypertensive patients with at least one other risk factor for coronary heart disease. Investigators found no difference between groups on the primary outcome of fatal coronary heart disease or nonfatal MI.

In this analysis, the ALLHAT group, led by Dr Paul K Whelton (Tulane University, New Orleans, LA), divided the ALLHAT population into those with diabetes (n=13 101), IFG (1399), and normoglycemia (17 012) based on national guideline definitions.

They found no significant difference in the relative risk for the primary outcome among diabetic or normoglycemic patients who were assigned to lisinopril or amlodipine vs chlorthalidone or among the IFG patients assigned to lisinopril vs chlorthalidone. However, there was a significant increase in primary-outcome events for IFG patients assigned to amlodipine vs chlorthalidone, they report (relative risk 1.73 [95% CI 1.10-2.72]).

Stroke was more frequent in normoglycemic patients assigned to lisinopril vs chlorthalidone (RR 1.31 [95% CI 1.10-1.57]). Heart failure was also more common among patients with diabetes and normoglycemic patients assigned to either lisinopril or amlodipine vs chlorthalidone.

"Recognizing the constraints in the interpretation of clinical trials, the ALLHAT findings suggest that thiazide-type diuretics should be strongly considered as first-step agents for therapy in patients with hypertension and DM or IFG," the authors write. "These agents are not only efficacious but have been evaluated in many trials and are the least expensive medications to prescribe."

"Independent of diabetes status, our results suggest that diuretics are better than ACE inhibitors and calcium channel blockers in preventing certain cardiovascular-disease complications—especially heart failure—during initial treatment of high blood pressure," Whelton concluded in a statement from Tulane.

In their report, however, the BPLTTC group find what they describe in a press release as "little difference" in short- to-medium term cardiovascular events between any of diuretics/beta blockers, ACE inhibitors, ARBs, and calcium-channel blockers.

"A number of guidelines recommend lower blood-pressure goals and specific drug types for diabetic patients," Prof Bruce Neal (George Institute for International Health, University of Sydney, Australia), one of the study's authors, comments in a press release. "What we've discovered is that it is more important for clinicians to focus on achieving really effective blood-pressure lowering rather than worrying too much about which agents to use."

The BPLTTC is an ongoing project that collects and analyzes data from many large randomized trials; several reports from this group have been previously published. In this analysis, 27 randomized trials—including ALLHAT—were considered, and outcomes in terms of cardiovascular events and death were compared for diuretics/beta blockers, ACE inhibitors, ARBs, and calcium-channel blockers. The trials included a total of 158 700 patients, 33 395 of whom had diabetes.

"Total major cardiovascular events were reduced to a comparable extent in individuals with and without diabetes" by regimens based on any of these four groups of agents, the investigators, with corresponding author Dr Fiona Turnbull (George Institute for International Health), report. There was "limited evidence" that lower BP goals led to further reductions in total major CV events among those with and without diabetes, they added.

The authors point out that possible differential effects on intermediate renal outcomes that were not evaluated in these overviews "may still provide a rationale for using specific drug classes in patients with diabetes."

"In conclusion, small differences in the effects of regimens on macrovascular events cannot be excluded even by overviews of this magnitude, but it does seem that clinicians can be reassured that any of the major classes of BP-lowering agents are likely to produce substantial reductions in the short- to medium-term risks of the leading causes of death and disability in patients with diabetes," they write.

However, they also touch on the issue of cost between the agents. "These data should also have important implications for the treatment of patients with diabetes in resource-poor settings, where the cost of BP-lowering agents may be a key consideration."

New diabetes during antihypertensive therapy: Does it make a difference? San Francisco, CA - Still a matter for debate in the hypertension community is the clinical import of new diabetes mellitus that develops during antihypertensive treatment, particularly with diuretics and beta blockers. During the recent annual meeting of the American Society of Hypertension 20th Annual Scientific Session, veteran defender of diuretics Dr Marvin Moser (Yale University School of Medicine, New Haven, CT) took on Dr Paolo Verdecchia (Universit di Perugia, Italy) in a debate on this issue. Drs Paolo Verdecchia and Marvin Moser Verdecchia was first author on a recent publication suggesting that the development of new diabetes during treatment for hypertension presages a risk for CVD events of 44% per year, not dissimilar from patients with previously diagnosed diabetes [4]. Plasma glucose at baseline and diuretic treatment were independent predictors of new diabetes in their analysis. The issue has been a hot topic since ALLHAT trial investigators and subsequent clinical guidelines from JNC 7 concluded that diuretics should be considered as a first choice for antihypertensive therapy for most patients. Although results for the primary end point in that trial were identical for all of diuretics, amlodipine, and lisinopril, advantages on some secondary outcomes and the much lower cost of diuretics gave them the edge over the other drugs, ALLHAT investigators concluded. However, it is also the case that diuretics and beta blockers cause more new-onset diabetes than these other agents, leading to the debate over this issue. In his remarks, Verdecchia acknowledged that although new-onset diabetes is more frequent with diuretics and beta blockers than these other agents, "this point has perhaps been emphasized too much, because if one calculates the excess risk of CV events associated with new-onset diabetes (in ALLHAT), probably these events are only 2% of the total CV events in that treatment group," he said. "So it's like a drop in the ocean" in terms of its impact on outcomes in ALLHAT. However, he added, follow-up in the trial was only three to four years, perhaps not long enough for events associated with the new diabetes to become manifest. Verdecchia pointed out that those patients who are at high risk for new-onset diabetes can easily be identified using such clinical predictors as low HDL cholesterol and elevated glucose—"and in these subjects we should be careful." Preventive measures such as increased physical activity and appropriate diet should be recommended, he said, "and if these patients are really at high risk of developing new diabetes, particularly if they're young and might hopefully have many years to live, we should begin treatment with drugs different from diuretics and beta blockers, possibly an ACE inhibitor, and reserve the diuretics for the second or third step, but starting with a low dose." Moser acknowledged that diuretics and beta blockers do increase the risk for new-onset diabetes compared with other drugs. "But I think to attempt to change people's treatment patterns is wrong, based on new-onset diabetes," he said, "because despite the study that you've just heard about, that was very carefully done, there are studies that have not shown that." The Systolic Hypertension in the Elderly Program (SHEP) study, for example, with 14 years of follow-up, did not show that new-onset diabetes had the same prognosis as diabetes at baseline and that patients treated with diuretics with a beta blocker added had improved outcomes. "In other words, there's evidence that even though you might increase new-onset diabetes, you do not affect cardiovascular outcomes, and I think that's the bottom line." Similarly, in the ALLHAT study, "which has been much maligned," he said, "if you forget the subsets, forget the fact that diuretics are better with heart failure and better with stroke, just take the primary outcome . . . whether you were diabetic or not, you benefited." "As some of you may know, I've been defending diuretics for about 100 years," Moser said wryly. Various allegations have been leveled against these drugs over the years, including that they reduce stroke but not MI because of their effects on glucose or cholesterol or that they don't reverse left ventricular hypertrophy, he said. "All of these have proven false." He conceded that he can "conceive of" patients in whom treatment might begin with an ACE inhibitor or ARB or even beta blockers in those with angina and BP elevation, although eventually a diuretic would probably need to be added to get the blood pressure down. "But it shouldn't be the focused argument about a diuretic vs other drugs," Moser said. "I think the new-onset diabetes is real, and Paolo's data are important, but I think it's another attempt to say 'my drug is better than your drug' and I think we should go beyond that." -SJ