CardioExchange Archive

Multiple randomized clinical trials conducted in patients with type 2 diabetes showed that intensive glucose control reduces composite endpoints of microvascular disease, primarily driven by reductions in albuminuria. None, so far, has established the effect of intensive glucose control on macrovascular clinical outcomes, such as end-stage renal disease (ESRD) or death from renal disease. Even when trial data were aggregated in a meta-analysis of over 28,000 patients, the evidence for a significant effect on renal outcomes was lacking.

Perkovic and colleagues now report “the strongest evidence yet that intensive glucose-lowering regimens may protect against the development of ESRD.” The investigators analyzed data from the ADVANCE trial to determine the effect of an intensive glucose control strategy (target HbA_1c, ≤6.5%; achieved HbA_1c, 6.5%) compared with standard care (defined by local guidelines; achieved HbA_1c, 7.3%) on multiple renal outcomes, including ESRD (defined as need for dialysis or renal transplantation), renal death, renal death or ESRD, sustained or any doubling of creatinine to >200 mmol/L, new micro- or macroalbuminuria, and progression or regression of albuminuria. They found modest but significant reductions in new micro- and macroalbuminuria, but no effect on doubling of creatinine. However, they did find a significant reduction in ESRD, with an associated hazard ratio of 0.35 (95% CI, 0.15–0.83).

Are we convinced that intensive glucose lowering strategies will reduce the need for dialysis or transplantation?

Here are a few things to consider:

1. Only 27 ESRD events occurred, so the absolute risk for ESRD was extremely low. Among 11,140 participants with type 2 diabetes followed over 5 years, the annual event rates of ESRD were 0.075% in the standard group versus 0.026% in the intensively treated group. This means that 410 persons would need to be intensively treated over 5 years to prevent 1 ESRD event.
2. Multiple renal endpoints were tested in this post-hoc analysis — without adjustment for multiple comparisons. In this context, it is tough to consider the results more than simply hypothesis-generating. Furthermore, as noted above, when evidence from ADVANCE and other randomized controlled trials was considered together in a meta-analysis, the results were not significant for ESRD.
3. Even if we accept that out of 410 intensively treated patients, 1 ESRD event will be prevented, does this benefit outweigh the risks? Intensive glucose strategies increase the risk for severe hypoglycemia requiring external assistance. Although the incidence of hypoglycemia varied considerably across trials, a conservative estimate would place a number needed to be harmed at about 50 (and this number may underestimate hypoglycemia that may occur in community settings). In addition, the ACCORD study was terminated early because of an increased rate of mortality in intensively treated patients, with 1 extra death per 95 patients treated for 3.5 years.

The analysis conducted by Perkovic et al. may be the strongest evidence yet, but it doesn’t provide compelling reasons to recommend intensive glucose control for prevention of ESRD in type 2 diabetes patients like those enrolled in ADVANCE.