Dr. Breay W. Paty (biography and disclosures)
What I Did Before
Tight glucose control (reflected in A1C), reduces the risk of microvascular complications, such as retinopathy, nephropathy and neuropathy in patients with diabetes. This relationship holds true even to A1C levels below 7%. Until recently, many assumed that tight glucose control also reduced the risk of cardiovascular disease (CVD) in diabetes. For this reason, in the past, I would target an A1C as low as possible (even below 6.5%) for all my patients with diabetes in order to minimize both microvascular and macrovascular (CVD) complications. However, recent studies suggest that the relationship between glucose control (A1C) and cardiovascular disease is more complex than we may have realized.
What Changed My Practice
The ACCORD and ADVANCE studies were large (>10,000 subjects) multicentre trials, which examined the effect of tighter glucose control on CVD endpoints (nonfatal MI, nonfatal stroke or cardiovascular death) in older type 2 diabetes subjects. Using multiple glucose lowering therapies (including TZDs and insulin), the ACCORD trial achieved an average A1C of 6.4% in the intensively treated group (vs. 7.5% in the standard group). The trial was stopped early, because of a statistical increase in overall death (a secondary outcome) in the intensively treated patients. Most of these deaths appeared to be from cardiovascular causes, but the underlying reason for the increase in mortality was not clear. The ADVANCE study achieved an A1C of 6.5% in the intensive group (vs. 7.3% in the standard group), but did not show a significant difference in overall or cardiovascular mortality. A third, smaller study, VADT, also did not show a difference in CVD or death between the more intensively treated patients (A1C 6.9%) vs. the standard group (A1C 8.4%). There were a number of limitations to each of these studies, but the overall results suggested that tighter glucose control did not seem to reduce CVD events in older patients with established type 2 diabetes. However, a subsequent meta-analysis including these 3 trials, along with UKPDS and PROactive, showed a statistical reduction in MI and cardiovascular death in intensively treated patients, but with no difference in overall mortality. Furthermore, longer-term follow-up of UKPDS patients seemed to show benefit to earlier intensive therapy.
What I Do Now
Based on these results, I now tailor glucose targets more specifically to each patient. It appears that once CVD is established (i.e. older patients with longer duration of diabetes), the benefits of intensive glucose-lowering therapy are not as clear. However, tighter glucose control still seems to improve CVD risk in younger patients with less established disease. For younger patients with no pre-existing CVD or other significant risk factors (hypertension, smoking, family history of CVD), I continue to target an A1C below 7% (especially if it can be easily achieved). However, for older patients (> 50 years), with a longer duration of diabetes (> 15 years), I target an A1C of ~7%, but no lower. This target will avoid the potential downsides of intensive therapy (such as hypoglycemia and possible increased CVD risk), while still providing protection against microvascular disease. Finally, for patients with significant comorbid illness and a limited life expectancy, I target a higher A1C 7.5-8%. In this way, I try to avoid the burden and risk of intensive therapy, if the patient is not likely to see a benefit.
References: (Note: Article requests require a login ID with CPSBC or UBC)
- The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 2008; 358: 2545-59. (View article with CPSBC or UBC)
- The ADVANCE Collaborative Group. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2008; 358:2560-72. (View article with CPSBC or UBC)
- Duckworth W. Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med 2009; 360 (2): 129-39. (View article with CPSBC or UBC)
- Ray K, Seshasai SR, Wijesuriya S, et al. Eff ect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373: 1765–72. (View article with CPSBC or UBC)