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Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes
Study Questions:
Among surviving patients from the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, what is the impact of blood pressure–lowering therapy and intensive glucose control on cardiovascular outcomes at 6-year post-trial follow-up?
Methods:
This was a post-trial follow-up study of all surviving patients from the ADVANCE trial. ADVANCE was a multicenter, international trial in which 11,140 patients with type 2 diabetes mellitus and at least one additional risk factor for cardiovascular disease were randomly assigned to a single-pill (fixed-dose) combination of perindopril (4 mg) and indapamide (1.25 mg) or matching placebo, and were also randomly assigned to a gliclazide (modified release)-based intensive glucose control regimen (targeted to achieve a glycated hemoglobin level of 6.5% or lower) or to standard glucose control. Primary outcomes were death from any cause and major macrovascular events (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from any cardiovascular cause). Endpoints during the post-trial follow-up were not adjudicated.
Results:
Of 10,261 participants who were alive when the blood pressure–lowering comparison was completed and the 10,082 patients who were alive when the glucose control comparison was completed, 8,494 participants enrolled in the post-trial follow-up. Post-trial follow-up was 5.9 years and 5.4 years in the blood pressure–lowering comparison group and the glucose control comparison group, respectively. In participants randomized to blood pressure lowering, there was a significant, but attenuated cumulative benefit with respect to the incidence of death from any cause that extended up to the end of the overall follow-up period (hazard ratio, 0.91; 95% confidence interval, 0.84-0.99; p = 0.03). In the original trial, the average difference in blood pressure was 5.6/2.2 mm Hg between the perindopril-indapamide and placebo groups. There were no differences in the primary outcomes between the intensive glucose control and standard glucose control groups. In participants randomized to intensive glucose control, there was a significant benefit with respect to end-stage renal disease (hazard ratio, 0.54; 95% confidence interval, 0.34-0.85; p = 0.0007).
Conclusions:
At 6 years of post-trial follow-up in the ADVANCE trial, blood pressure–lowering therapy was associated with a significant (but attenuated) reduction in mortality, but intensive glucose control did not reduce the risk of the primary outcomes.
Perspective:
This is a valuable study that demonstrates significant reductions in the rates of death from any cause and from cardiovascular causes resulting from a 4.5-year duration of blood pressure–lowering therapy with perindopril-indapamide. As the authors discuss, the results offer insight into the carry-forward effect and intuitively suggest that the ‘gradual attenuation of benefits over time reinforce the importance of continuing blood pressure–lowering medications if the benefits of treatment are to be fully realized.’ Although the long-term ADVANCE results, which do not demonstrate long-term beneficial effects of earlier periods of intensive glucose control stand in contrast to other studies (e.g., DCCT-EDIC and UKPDS), the authors offer several plausible explanations for the varying outcomes, including differences in baseline glycated hemoglobin levels (>8.5% in both DCCT and UKPDS trials vs. a 7.5% baseline level in the ADVANCE trial).
Keywords: Perindopril, Myocardial Infarction, Stroke, Follow-Up Studies, Kidney Failure, Chronic, Diabetes Mellitus, Type 2, Blood Pressure, Risk Factors, Glucose, Glycated Hemoglobin A, Drug Combinations, Gliclazide, Indapamide, Confidence Intervals
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