ADVANCE: Blood Pressure Lowering in Diabetes

Response: In response to the letter to the editor by Patel and associates, we are aware of the ADVANCE trial and its findings, as noted in an earlier editorial by one of the authors.1 As noted in that editorial, it is known that achieving a lower blood pressure value than that of a comparator group in a clinical trial yields lower cardiovascular disease event rates in persons with type 2 diabetes.2, 3 Moreover, ACE inhibitors, generally with a thiazide diuretic, reduce cardiovascular events in proportion to their blood pressure–lowering effect regardless of whether patients have diabetes and hypertension or baseline essential hypertension.4, 5 Moreover, until the recent results of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial,6 the best data available from the Oxford Trialist group supports the notion that no antihypertensive agent, drug class, or combination of agents is better than another.7 The ADVANCE trial largely confirms these findings. Because the mean blood pressure of ADVANCE trial participants was lower than that of participants in previous trials, the ADVANCE trial does provide new evidence that starting antihypertensive therapy at an earlier prehypertensive stage in patients with type 2 diabetes is beneficial. However, the authors’ claim that this trial establishes the place for a fixed, low-dose ACE inhibitor/thiazide combination pill in all patients with type 2 diabetes is probably premature. The observed effects were more likely the result of a greater reduction in blood pressure in patients receiving active treatment than of properties specific to the combination of perindopril and indapamide or to a combination of any ACE inhibitor and thiazide diuretic. This would certainly be supported by the results of the diabetes subgroup of ACCOMPLISH, presented at the American Diabetes Association meeting in June 2008.8 Moreover, in the ADVANCE trial, the fixed-dose combination was compared with placebo, not with another active agent or agents, so the treatment-specific effects cannot be isolated from the clinically significant reduction in blood pressure in the active therapy group. Also, more than half of the patients randomly assigned to placebo ended up taking perindopril but were restricted by study design from taking thiazide diuretics, and they still had more outcome events. Therefore, the observed benefits of the combination relative to placebo (no thiazide diuretics) are at least in part the result of adding a thiazide diuretic to perindopril. This type of result was also seen in Perindopril Protection Against Recurrent Stoke Study (PROGRESS). The purpose of the ASH position paper was to present new information in the context of already established guidelines by organizations such as the American Diabetes Association and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). The ADVANCE trial made the point that the relatively lower blood pressure values achieved earlier in the disease course result in fewer outcomes; that is an important point and supports the hypothesis already well accepted by physicians. Likewise, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure results should also be instructive regarding the cardiovascular disease risk–decreasing benefits of reducing systolic blood pressure to <120 mm Hg rather than the current goal of <130 mm Hg in patients with diabetes and hypertension.9 While the ADVANCE study was an important study that will provide a strong impetus for treating earlier in the course of disease, it would not change the paradigm of approach and, hence, was not included in our position paper.—