Piecing the puzzle together: ACCORDing to whom?

For many people, the Diabetes Control and Complications Trial (DCCT) report 15 yr ago ended controversy about the relationship between glucose control and microvascular complications (1). At the time, this debate was a one-piece puzzle, seemingly solved by the study. However, to others, the puzzle was more complex. Because DCCT was a type 1 study, concerns were raised that the weight gain often seen with intensive therapy could result in more cardiovascular events in patients with type 2 diabetes. These concerns were alleviated with the report of the United Kingdom Prospective Diabetes Study (UKPDS) 10 yr ago (2). Like the DCCT, improvements in glycemia resulted in a reduced microvascular burden, but in this older type 2 population, there was also a nonsignificant 16% reduction in myocardial infarctions. Yet another piece to the puzzle was added with a Japanese report confirming the relationship between tight glucose control and microvascular complications. This trial also noted twice the number of macrovascular events in the conventional therapy group as opposed to those intensively managed, but the number of events was small (1.3 vs. 0.6 events per 100 patient-years), as would have been expected in this relatively young cohort (3). It was surprising to some that intensive therapy of glycemia did not more convincingly reduce cardiovascular events in type 2 diabetes. Some argued we were using the wrong agents and suggested that perhaps using a novel drug class such as thiazolidinediones would improve cardiovascular event rates. Unfortunately, the use of pioglitazone in the PROactive study did not improve a composite cardiovascular disease (CVD) primary endpoint (4), and interpretation of the study results generated much controversy. Perhaps a better way to solve the puzzle is by using a more comprehensive strategy of treating not just glycemia but also blood pressure and lipids in patients with type 2 diabetes. The group from the Steno Diabetes Center recently published their 13.3-yr follow-up of 160 subjects with type 2 diabetes and microalbuminuria (5). The results after completion of the intervention addressing all three risk factors, including behavior modification with more physical activity, were reported in 2003 after 7.8 yr of treatment (6). At that time, it was noted that the multicomponent intervention reduced CVD and microvascular events by about 50%. The more recent report, which was simply a follow-up observation study without active intervention, noted that the intensive therapy group had a reduction in mortality (hazard ratio 0.54; 95% confidence interval 0.32–0.89; P 0.02) (5). Intensive therapy was also associated with a lower risk of CVD deaths and events as well as reductions in the microvascular outcomes of end-stage renal disease and need for retinal photocoagulation. Before leaving this part of the puzzle, several points need to be emphasized. First, the Steno-2 population is a very specific population: white, microalbuminuric patients who at the beginning of the study were 55 yr old. For glycemic control of the intensive therapy group, fewer than 20% were able to achieve the target of less than 6.5% hemoglobin A1c (A1C), and overall mean A1C was about 8% for these subjects during both the intervention and the follow-up (5, 6). The difference in A1C of 0.7% between these two groups during the intervention likely explains part, if not most, of the microvascular benefit. Importantly, like the Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the type 1 DCCT cohort (7), there was continuing microvascular benefit years later for those patients randomized to intensive therapy, despite the fact that A1C levels were no different after the intervention. Besides the importance of metabolic memory, which was initially described for the EDIC patients with type 1 diabetes, this effect further speaks to the clinical importance that any improvement in glycemic control will be important, even if A1C levels are not at target. The Steno-2 conventionally treated patients also remind us just how poor the prognosis of type 2 diabetes with microalbuminuria really is; at the end of the follow-up period, the rate of death was 50% (5). The good news is there was an absolute risk reduction of 20% for death from any cause and 29% for any cardiovascular event with this intensive therapy. It is difficult to quantify the contribution of each component of therapy to the