ADVANCE-ON: Follow-up of blood-pressure lowering and glucose control in type 2 diabetes

Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;[epub ahead of print]. doi: 10.1056/NEJMoa1407963.


The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational Study (ADVANCE-ON) was a 6-year follow-up of the ADVANCE cohort that assessed whether there are long-term benefits to routine blood pressure lowering and intensive glucose control in subjects with type 2 diabetes.  


 
After the final ADVANCE visit, all patients discontinued their randomly assigned interventions and resumed usual care. Total median follow-up was 9.9 years for both interventions. The co-primary outcomes were all-cause mortality and a composite of major macrovascular events.

 
Baseline characteristics were similar for subjects in ADVANCE and ADVANCE-ON, apart from such changes as are consistent with a healthy-survivor effect in the post-trial cohort. The mean between-group difference in BP observed during ADVANCE (5.6/2.2 mm Hg, P<0.001) was no longer evident 6 months after the end of that part of the trial. 

 
After completion of the BP-lowering comparison of the trial, the use of perindopril/indapamide, other BP-lowering therapies, and other medications was well balanced between subjects originally assigned to perindopril/indapamide vs placebo.

 
After completion of the glucose-control comparison of the trial, the use of oral glucose-lowering therapies and insulin in subjects originally assigned to intensive vs standard control converged, although some differences remained. Insulin use increased more in the standard- vs intensive-control group. Sulfonylurea use decreased in both groups over time.

 
The mean between-group difference in A1C (0.67 percentage points, P<0.001) observed during ADVANCE was no longer evident by the first post-trial visit (average 2.9 years later).
  • 0.08 percentage points; 95% CI, −0.07 to 0.22; P=0.29
  • Levels remained similar at the conclusion of the post-trial follow-up (7.2% intensive and 7.4% standard)

Primary Outcomes in the Blood-Pressure–Lowering Cohort 

During the randomized blood-pressure intervention, 879 patients died, and 1,000 patients had a major macrovascular event. During the post-trial follow-up period, an additional 1,386 patients died, and 1,166 patients had an incident major macrovascular event. There was a significant but attenuated cumulative benefit for all-cause mortality that extended to the end of the overall follow-up period among subjects assigned to perindopril/indapamide. No evidence suggested that the cumulative effects for all-cause mortality varied according to the subgroups studied, including the subgroup assigned to intensive versus standard glucose control (P>0.20 for interaction for all subgroup analyses).

Secondary Outcomes in the Blood-Pressure–Lowering Cohort 

In the blood-pressure–lowering cohort, an additional 520 deaths from cardiovascular causes, 393 myocardial infarctions, and 538 strokes were recorded during the post-trial period. The in-trial reduction in the risk of cardiovascular mortality among those assigned perindopril/indapamide was attenuated but remained significant at the end of the overall follow-up period. There was no benefit with respect to any other secondary outcomes. No significant interaction was found between the effects of glucose control and blood-pressure lowering for any primary or secondary outcome (P>0.10 for interaction for all comparisons).

Primary and Secondary Outcomes in the Intensive Glucose Control Cohort 

During the randomized glucose-control intervention, 1,031 patients died, and 1,147 patients recorded a major macrovascular event. During the post-trial period, an additional 1,234 patients died, and 1,019 patients recorded a major macrovascular event. No cumulative benefits of intensive glucose control for all-cause mortality or major macrovascular events, either in-trial or after follow-up, were noted. No evidence was found to suggest that the cumulative effects for all-cause mortality varied according to the patient subgroups studied, including the subgroup assigned to active blood-pressure–lowering therapy versus placebo (P>0.10 for interaction for all subgroup analyses).

 
During the post-trial period, an additional 349 major clinical microvascular events were recorded. There were no cumulative benefits for major clinical microvascular events or severe diabetes-related eye disease (not shown). A significant cumulative benefit for to end-stage renal disease was seen (HR, 0.54; 95% CI, 0.34-0.85; P=0.007). A significant difference for in-trial and overall rates of major hypoglycemia was noted, but no difference was evident hen the post-trial period was considered separately. No cumulative benefit was seen for death from renal disease or any other secondary outcome, including death from cardiovascular causes, myocardial infarction, and stroke There was no significant interaction between the effects of glucose control and blood-pressure lowering with respect to any primary or secondary outcome (P>0.10 for interaction for all comparisons).

Clinical Significance for HCPs 

  • After nearly 10 years of follow-up, a 4.5-year period of blood-pressure–lowering treatment resulted in an attenuated but significant reduction in the rates of death from any cause and death from cardiovascular causes
    • The attenuation of the benefit of blood-pressure–lowering treatment over time reinforces the importance of continuing medication if the full benefit is to be realized
     
  • No significant benefit with respect to mortality, macrovascular events, or microvascular events was observed from a 5-year period of intensive glucose control
Click slide to view larger. 
ADVANCE-ON: Summary Clinical Significance for HCPs  
ADVANCE-ON: Summary Clinical Significance for HCPs 

 
The fixed-dose combination of perindopril and indapamide used in ADVANCE and ADVANCE-ON is not FDA-approved in the United States.
 
All slides available for download in the slide library. 
 

Related content: 

For more content on ADVANCE, click here 

  

Any pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual prescribing information for approved uses outside of the United States. 

October 2014 

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.  

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Last Modified: 10/17/2014