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COMMENTARY |
University of Washington School of Medicine, Seattle, Washington 98105
Address all correspondence and requests for reprints to: Irl B. Hirsch, M.D., University of Washington School of Medicine-Roosevelt, 4225 Roosevelt Avenue Northeast, Suite 101, Seattle, Washington 98105. E-mail: ihirsch{at}u.washington.edu.
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 outcomes, but from a practical point of view, it suggests our attempts to improve all risk factors results in a benefit.
So on the day Steno-2 put a nice piece of our seemingly simple puzzle into place, we also learned about the first results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study through a press release and news conference (8). In ACCORD, 10,251 high-risk patients with type 2 diabetes were randomized into three different subtrials, each with a different intervention. Although the hypertension and lipid trial continue as planned, the glycemia trial terminated prematurely due to results that contradicted what many people predicted: there were 257 deaths in the intensive glycemic therapy group attempting a goal A1C of less than 6%, compared with 203 deaths in the standard treatment group, assigned to maintain their A1C from 7–7.9%. This is a difference of three per 1000 participants per year, over an average of almost 4 yr of treatment. Importantly, death rates in both groups were lower than seen in similar populations, and no single drug, including rosiglitazone, or combination of drugs was found to be responsible for the increase in death.
Did our puzzle just break? Or is there a solution that fits the new piece from ACCORD? Or are we working on the wrong puzzle entirely? At this time, of course, the study has not even been published, but one can speculate on this important finding. We have to remember this is a very different population than the UKPDS or Japanese studies. In the United Kingdom study, median age at entry was 54 yr. Importantly, these patients were biased against having baseline CVD in that they were newly diagnosed with their diabetes, and they were excluded if they had a cardiovascular event during the past year. In the Japanese study, the subjects were significantly younger with mean age in the late 40s and low rates of cardiovascular events. Compare these two studies with ACCORD, in which mean age was 62 yr, diabetes duration was 10 yr, and patients either had already had a known CVD event or two CVD risk factors. So ACCORD was a more fragile population than the United Kingdom and Japanese studies but one more similar to the PROactive study, in which the mean age was 61 yr with 9.5 yr duration of diabetes and half with known CVD at baseline (4). One difference between PROactive and ACCORD is that the intervention group of the former study had a mean final A1C of 7%, significantly higher than what was reported for the ACCORD intervention subjects.
So how can one explain the counterintuitive ACCORD results? The press release said that hypoglycemia was not responsible, yet we have learned with continuous glucose monitoring that asymptomatic hypoglycemia is not uncommon, particularly in patients with near-normal A1C levels. It will be interesting to learn what proportion of events occurred in the hospital, during or after a medical or surgical procedure due to evolving data that hypoglycemia is perhaps more deleterious in this population. We also have to wonder how weight gain may have factored into these results. Three of the treatments, namely sulfonylureas, thiazolidinediones, and insulin, all result in weight gain, and we need to confirm that this factor did not promote more CVD events.
The early ACCORD finding also raises an even more fundamental question. Even if obesity is found to be detrimental in these patients, why do the results of this study move in the opposite direction of the UKPDS? One has to believe the key issue here is the specifics of the population at baseline. In the British study, baseline CVD was uncommon, because patients were younger with newly diagnosed diabetes. In ACCORD, patients at baseline either had known CVD or additional risk factors. For those without known disease at baseline (a primary prevention cohort), we need to know if they fared differently from those entering with a preexisting disease, in effect a secondary intervention cohort. Perhaps this will turn out to be an important piece of the puzzle.
There is yet another known vascular pathophysiology that needs to be recalled. Over 25 yr ago, there were several alarming reports of diabetic retinopathy worsening with improved glucose control, a phenomenon that was also noted in the DCCT. Over time, even in these DCCT patients, retinopathy improved if the improvement in control was sustained. The exact mechanism for this early microvascular worsening is unknown, but evidence to date suggests the improved control reduces blood flow, inducing anoxia to tissue that is already hypoxic (9). Alternatively, changes in IGF-I may be involved. It is clear that even with retinopathy, worsening of disease does not occur unless baseline disease is already present when the improved control is initiated. This may very well be relevant to the ACCORD intensive-therapy patients who already had baseline CVD when starting the study.
Another area of interest is the role of glycemic variability in the pathogenesis of the ACCORD results. It appears that glucose variability induces oxidative stress, which is obviously a concern for someone with a high risk for vascular complications. However, to date, the data supporting this as an independent risk factor for vascular complications are inconclusive. ACCORD could help to clarify this, even with data from home glucose monitoring, because new mathematical tools have been developed specifically for this technology (10).
It is premature to reach any definitive conclusions until we see the actual data published, and it will likely be quite some time before all of our questions are answered. Nevertheless, the relationship between progression of macrovascular disease and glycemic control is a much more complicated puzzle than originally appreciated. Although the frame and many parts are already in place, more pieces to the puzzle will be completed once the ACCORD data are published, in addition to two other trials that should have initial results in the near future. The Veterans Affairs Diabetes Trial in the United States and the multinational Action in Diabetes and Vascular Disease will contribute to our understanding, but it is unlikely that the puzzle will be completely finished even after the publication of all three of these studies. However, it seems clear that we may very well have different glycemic targets for different populations of patients, as opposed to our current strategy of attempting to achieve a specific A1C target for the majority of our patients. Let’s hope that, in time, the pieces all fit and the puzzle’s picture is clear.
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Footnotes |
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Abbreviations: A1C, Hemoglobin A1c; ACCORD, Action to Control Cardiovascular Risk in Diabetes; CVD, cardiovascular disease; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; UKPDS, United Kingdom Prospective Diabetes Study.
Received February 10, 2008.
Accepted February 10, 2008.
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