Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes

Posted by • October 10th, 2014

In a follow-up study of patients with type 2 diabetes, mortality benefits in those originally assigned to antihypertensive therapy were evident at the end of follow-up, but in-trial glucose differences did not result in long-term benefits in mortality or macrovascular events.

Post-trial follow-up studies of patients with diabetes have previously reported long-term beneficial effects of earlier periods of intensive glucose control, but not blood-pressure lowering, on a range of outcomes, including mortality and macrovascular events.

Clinical Pearls

What were the primary results of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial?

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial assessed the effects of routine blood-pressure lowering and intensive glucose control in a broad cross section of patients with type 2 diabetes. Routine administration of a single-pill (fixed-dose) combination of perindopril and indapamide was associated with a reduction in the risk of the primary composite end point of major macrovascular or microvascular events. Reductions in the risks of death from any cause, cardiovascular death, and nephropathy were also observed. Intensive glucose control was associated with a reduction in the risk of the primary composite end point of major macrovascular or microvascular events, owing primarily to a reduction in the incidence of new or worsening nephropathy. This benefit for nephropathy included a reduction of end-stage renal disease but not of renal death. No clear protective or harmful effects of intensive glucose control on death from any cause or major macrovascular events were identified.

What were the results of this post-trial follow up of the ADVANCE-Observational Study in the group assigned to a 4.5-year period of blood-pressure lowering treatment with perindopril-indapamide?

Consistent with the in-trial finding of a significant risk reduction of 14% for death from any cause for those assigned to erindopril-indapamide therapy (hazard ratio, 0.86; 95% CI, 0.75 to 0.98; P=0.03), there was a significant but attenuated cumulative benefit for death from any cause to the end of overall follow-up (hazard ratio, 0.91; 95% CI, 0.84 to 0.99; P=0.03). There was no cumulative benefit of perindopril-indapamide for major macrovascular events, and the hazard ratios for this composite outcome were similar at the end of the in-trial and at the end of overall follow-up periods, though not significant at either time. The in-trial reduction in the risk of cardiovascular death recorded for those assigned to perindopril-indapamide (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) was attenuated but remained significant at the end of the overall follow-up period. There were no cumulative benefits for any other secondary outcome, including major clinical microvascular events.

Table 2. Primary and Secondary Outcomes during the Randomized Trial and Overall in the Blood-Pressure-Lowering Cohort and the Glucose-Control Cohort.

Figure 1. Cumulative Incidence of Events, According to Blood-Pressure-Lowering Study Group.

Figure 2. Hazard Ratios for Events, According to Blood-Pressure-Lowering Study Group.

Morning Report Questions

Q: What were the results of post-trial follow-up in the group who had received intensive glucose control?

A: Consistent with in-trial findings, there were no cumulative benefits of intensive glucose control for either death from any cause or major macrovascular events. There were no cumulative benefits for major clinical microvascular events or severe diabetes-related eye disease. There was a significant cumulative benefit with respect to end-stage renal disease (hazard ratio, 0.54; 95% CI, 0.34 to 0.85; P=0.007), although relatively few events were recorded. There was no cumulative benefit for renal death. There were no cumulative benefits for any other secondary outcome, including cardiovascular death, myocardial infarction and stroke.

Table 2. Primary and Secondary Outcomes during the Randomized Trial and Overall in the Blood-Pressure-Lowering Cohort and the Glucose-Control Cohort.

Figure 3. Cumulative Incidence of Events, According to Glucose-Control Study Group.

Figure 4. Hazard Ratios for Events, According to Glucose-Control Study Group.

Q: What do the authors postulate as the reason for the divergent outcomes of this study compared to other glucose control studies in diabetes?

A: The Epidemiology of Diabetes Interventions and Complications (EDIC) study, an extension of the Diabetes Intervention and Complications Trial (DCCT), and United Kingdom Prospective Diabetes Study (UKPDS) post-trial follow-up studies reported the emergence of long-term beneficial effects of earlier periods of intensive glucose control on macrovascular events and death. This study did not observe any such long-term benefits after post-trial follow-up. In explaining the divergent outcomes, the authors note that first, the younger patients with type 1 diabetes (in the DCCT-EDIC) or with newly diagnosed type 2 diabetes (in the UKPDS) may have been more likely to achieve long-term benefits from glucose lowering than the older patients with established disease included in the study. Second, there were differences between the studies in the in-trial levels of blood glucose, as reflected in the levels of glycated hemoglobin, which differed by an average of 0.67% over a period of 5 years in the ADVANCE trial, but were much larger in the DCCT (2.0% over a mean of 6.5 years during the trial) and slightly larger in the UKPDS (0.9% over a median of 10 years during the trial). Third, post-trial follow-up in this study (5 years) was shorter than for DCCT-EDIC and UKPDS (both >10 years) and may have been insufficient for benefits to emerge. Fourth, it is possible that more widespread use of effective background preventive therapy in the ADVANCE trial masked the long-term effects. Finally, competing risk, which is a greater issue for older patients than younger patients, may not have allowed the full effects of the glucose intervention to be observed in this study.

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