This meta-analysis of four large, randomised controlled trials of more- vs less-intensive glycaemic control in people with type 2 diabetes demonstrates a modest reduction in major macrovascular events with greater glucose lowering. Overall, intensive glycaemic control reduced the final visit HbA1c by a mean of 0.88 percentage points more than less-intensive glycaemic control, with an associated 9% (95% CI 1–16%) RR reduction for the composite major cardiovascular outcome of cardiovascular death or non-fatal stroke or non-fatal myocardial infarction during an average follow-up of 4.4 years. For fatal/non-fatal myocardial infarction alone, the RR reduction was 15% (95% CI 6–24%). The magnitude of these macrovascular risk reductions are consistent with the epidemiological relationship between HbA1c and cardiovascular events reported from observational studies in persons with diabetes [14–17].
Meta-analysis of the other secondary endpoints showed no significant overall effect on the risk of fatal/non-fatal stroke, hospitalised or fatal congestive heart failure or all-cause mortality. No significant effect was seen on cardiovascular death, although there was a 10% trend for an RR increase (HR 1.10, 95% CI 0.84–1.42), including point estimates of 1.35 and 1.32 for the ACCORD and VADT trials, respectively. These were the two trials that achieved and maintained the greatest differences in HbA1c. The significant heterogeneity among the four studies suggests that the possibility of harm with more-intensive glycaemic treatment cannot be ruled out.
Exploratory subgroup analyses of the impact of more-intensive glycaemic control on the composite major cardiovascular outcome showed no significant differences with respect to sex, age, initial HbA1c, duration of known diabetes or history of microvascular disease. Although of borderline significance, there was a suggestion that participants with no history of macrovascular disease achieved benefit, whereas those with prior macrovascular disease did not.
This meta-analysis also shows that allocation to a more-intensive glycaemic control regimen is associated with a more than twofold risk of major hypoglycaemia and that many glucose-lowering medications are generally required to achieve lower glycaemic targets. Whether these factors play a role in the effect of glycaemic control on cardiovascular outcomes clearly requires further investigation. Nevertheless, in conjunction with other reported benefits of glycaemic control in patients with type 2 diabetes [12, 18] the results presented here suggest some cardiovascular benefit for people with diabetes. This does not preclude the possibility that the balance of risks and benefits may vary for different patient groups. Indeed, evidence of statistical heterogeneity with respect to cardiovascular death among the trials (with the highest and lowest point estimates for the HR occurring in the ACCORD and ADVANCE studies, respectively), and the benefit on the composite major cardiovascular outcome in participants without, but not in participants with, prior macrovascular disease, suggest that either patient characteristics, the approach to glucose lowering or other measured (or unmeasured) variables may affect cardiovascular risk. Avoidance of severe hypoglycaemia in the setting of an intensive glycaemic control regimen, for example, clearly requires a particular set of patient capabilities.
The chief strengths of this analysis include its focus on the key primary and secondary outcomes in the trials, the large size of the trials, the consistency of results when analysed using different approaches, and the collaboration of the original trial investigators to produce data of the highest quality. In particular, it has been possible to ensure that definitions of outcomes and exposures are directly comparable, that analytic techniques are identical across the trials, and that subgroups are defined consistently. Furthermore, sharing of the data among study groups allowed for the independent analysis and confirmation of the results.
The ability to understand the heterogeneity among trials for some outcomes, however, remains limited by the number of trials and the limited power of the subgroup analyses. However, the fact that these trials differed in several ways is apparent in Tables 1, 2, 3, 4 and 5 and some of these differences may account for the observed heterogeneity. For example, the UKPDS was completed 10 years earlier than the other trials and studied patients with newly diagnosed vs established diabetes who were younger, lighter, more likely to be smokers, and on fewer cardioprotective drugs but at lower cardiovascular risk, and achieved a lesser contrast in the final visit HbA1c than the other three trials. Moreover, the four trials differed with respect to their mean on-trial difference in HbA1c (data not shown), the speed of HbA1c lowering, the mean difference in HbA1c reduction from baseline (Table 5), the methods by which this difference was achieved (Table 3), and the incidence rates of severe hypoglycaemia, which were also statistically heterogeneous (Table 5). They also differed with respect to the duration of exposure to the intervention, which may be an important determinant of its risks and benefits. Meta-analyses of trials using individual patient data can further explore these and other differences as possible explanations for the differential effect of intensive glucose control on myocardial infarctions vs cardiovascular death. However, these analyses were not available, as the ACCORD trial is still ongoing. Nevertheless, the exploration of the pooled data made possible by this collaboration of the four studies has generated the best estimate that is available currently of the cardiovascular benefits of more-intensive glycaemic control.
In conclusion, the recent publication of the findings from three major new trials of glucose-lowering and the UKPDS 10 year post-trial follow-up has provided important new insights into the balance of risks and benefits associated with the use of more-intensive glycaemic control in patient with type 2 diabetes. The meta-analysis presented here shows that more-intensive glycaemic control affords a modest but significant cardiovascular benefit in the short-to-medium term, although all-cause and cardiovascular mortality are not benefited. The effect on cardiovascular events is driven primarily by a 15% reduction in the risk of myocardial infarction.