The mean haemoglobin A1c concentration (HbA1c) was 0·9% lower for participants given intensive treatment than for those given standard treatment. Intensive glycaemic control resulted in a 17% reduction in events of non-fatal myocardial infarction (odds ratio 0·83, 95% CI 0·75–0·93), and a 15% reduction in events of coronary heart disease (0·85, 0·77–0·93). Intensive glycaemic control had no significant effect on events of stroke (0·93, 0·81–1·06) or all-cause mortality (1·02, 0·87–1·19).
So now we have modest evidence of macrovascular benefit from intensive glycemic control in DM 2. Microvascular benefits have been known for some time but macrovascular benefit has been elusive.
This meta-analysis is something of a mess, though, because of the heterogeneity of the five included studies in terms of patient populations, study objectives, intended targets and achieved targets:
ADVANCE, which demonstrated microvascular benefit and macrovascular neutrality, targeted a HgbA1C of 6.5%.
PROACTIVE did not set out to compare HgbA1C targets, but the treatment arm happened to achieve a HgbA1C of 6.9% as opposed to 7.5% in the placebo group, and was associated with macrovascular benefit.
VADT achieved a HgbA1C of 6.9% in the intensive treatment group vs 8.4% in the standard treatment group and was microvascularly and macrovascularly neutral.
UKPDS was associated with short and long term microvascular benefit and long term but not short term macrovascular benefit when the HgbA1C was targeted to 7%.
ACCORD was associated with increased cardiovascular (probably macrovascular) mortality in the ultraintensive (HgbA1C 6.4%) group. Microvascular outcomes were not reported.
What can we conclude? It appears that macrovascular benefits as compared to microvascular benefits attributable to intensive treatment of DM 2 are more modest and require longer duration of treatment. Some of the individual studies may have been underpowered or too short lived to demonstrate macrovascular benefit. PROACTIVE appears to be an anomaly because its results may reflect direct effects on serum lipids and endothelial function attributable to pioglitazone. ACCORD may be an anomaly owing to its very intensive and non-physiologic use of insulin in persons whose principal problem was insulin resistance and the metabolic syndrome. I have a great deal more to say about the latter issue in a post now in preparation.