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Vol. 55, No. 6, June 2009, pp.580 - 582 Copyright © 2009 by The College of Family Physicians of Canada
Is tight glycemic control in type 2 diabetes really worthwhile?YESMaureen Clement, MD CCFPFamily physician and diabetes specialist practising in Vernon, BC, a Clinical Assistant Professor at the University of British Columbia in Vancouver, and an Executive Member of the Clinical and Scientific Section of the Canadian Diabetes Association.
Onil Bhattacharyya, MD PhD CCFP
J. Robin Conway, MD
Correspondence: Dr M. Clement, Box 718, Armstrong, BC V0E 1B0; e-mailmaureenaclement{at}shaw.ca Since the first big landmark trial on glycemic control and complications in type 1 diabetes (DCCT [Diabetes Control and Complications Trial])1 was published in 1993, almost every major trial for type 1 and type 2 diabetes has consistently demonstrated the beneficial effects of lowering glucose on diabetes complications. According to large randomized trials, there is no question that the lower the hemoglobin A1c (HbA1c) levels, the lower the risk of microvascular disease.2 The relationship between macrovascular disease and increased glycemia has been shown in many epidemiologic studies, including the epidemiologic analysis of the relationship between HbA1c and vascular disease in the UKPDS (United Kingdom Prospective Diabetes Study).3 The EDIC (Epidemiology of Diabetes Intervention and Complications)4 trial, the 10-year posttrial monitoring of the DCCT, showed a 40% reduction in cardiovascular events and an almost 60% reduction in myocardial infarction (MI), stroke, and cardiovascular death in those patients who were, initially, intensively controlled compared with those less intensively controlled, even though their HbA1c values were the same at the end of the trial. (Although this study involved individuals with type 1 diabetes, it is in a sense a better demonstration of the singular effect of glucose lowering on macrovascular disease without the other confounding vascular risk factors found more frequently in type 2 diabetes.) Original data from the UKPDS, which included subjects with type 2 diabetes, showed a significant 25% reduction in microvascular complications (P = .0099) and a non-significant 16% reduction in MI (P = .052). In addition, the UKPDS’s 10-year follow-up5 continued to show a reduction in microvascular complications, despite similar HbA1c values between the intensive and control groups, during most of the posttrial period. There was also a significant reduction in MI (15%, P = .01) and death from any cause in the sulfonylurea insulin–treated group (13%, P = .007) and MI (33%, P = .005) and death from any cause (27%, P = .002) in the Metformin-treated group.
The implication is that tight glycemic control in newly diagnosed diabetes patients has a lasting effect on the reduction of both microvascular and macrovascular complications. This is the case even if glycemia increases over time. The same "legacy" effect seen in the EDIC trial and the UKPDS follow-up has also been demonstrated in the Steno-2 Study.6 This 8-year trial of a multifactorial risk-reduction strategy, including a target HbA1c value of 6.5%, clearly showed reduced macrovascular and microvascular complications with tight glycemic control. The 5-year follow-up study similarly showed a significant reduction in cardiovascular mortality (P = .04) and death from any cause (P = .02). So why the debate? One recent trial, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study,7 demonstrated a small increased risk of death in individuals with long-standing diabetes who were treated aggressively to target HbA1c levels of less than 6%; this has led to the question of whether or not tight glycemic control is worthwhile. Treating early gives the best benefits Three trials, designed to look at whether near-normal glycemic control reduces cardiovascular disease in type 2 diabetes, have just been completed. These are the ACCORD,7 the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation),8 and the VADT (Veterans Affairs Diabetes Trial)9 studies. There are 2 big differences between these studies and the ones mentioned previously. First, these trials were all short (3.5 to 5 years). Second, the patient populations in these 3 trials were older, had had diabetes for longer (eg, an average of 10 years in the ACCORD study), and were at higher risk of cardiovascular events, compared with the DCCT and UKPDS studies in which the patient populations were younger or recently diagnosed. All 3 trials were able to achieve sustained reductions in HbA1c levels for the duration of the studies, something that was difficult to achieve in previous trials, particularly the UKPDS. The ADVANCE study showed a significant reduction in microvascular complications (14%, 95% confidence interval 3% to 23%) and a non-significant reduction in the macrovascular events. By choosing an HbA1c target of 6.5%, there was a 21% reduction in new or worsening nephropathy. Neither the VADT nor the ADVANCE studies showed increased mortality or cardiovascular event rate; however, the ACCORD study, which attempted the most aggressive lowering of HbA1c levels (targeting < 6% in 6 months), showed a slight increase in deaths—1.7% versus 1.1%. This was, however, less than the predicted rate (4%), and overall the cardiovascular event rates in the intensive and standard groups (6.9% and 10.6%, respectively) were much lower than expected. Moreover, a prespecified subanalysis in the ACCORD study showed that patients treated intensively who showed the greatest reduction in primary macrovascular end points were at earlier stages of disease, with lower baseline HbA1c values and no known baseline vascular diseases.7 Likewise in the VADT study, those with the shortest duration of diabetes (< 15 years) benefited the most from intensive control.9 Don’t throw the baby out with the bathwater From the trials cited above, we can see that tight glycemic control in type 2 diabetes, with HbA1c target levels of less than 7%, reduces the microvascular complications of diabetes. It might also reduce macrovascular complications if initiated early, although it might take longer for the benefits to become evident. According to the Diabetes In Canada Evaluation (a study of diabetes care in primary practice),10 physicians have difficulty helping their patients to achieve HbA1c target values of less than 7%. The "headlines" of the ACCORD trial might suggest, to some, that physicians can "relax" in treating diabetes to target. This might be "throwing the baby out with the bathwater." As advocated in the 2008 Canadian Diabetes Association clinical practice guidelines,11 an HbA1c value of less than 7% will reduce microvascular complications. To further reduce the risk of nephropathy, an HbA1c value of less than 6.5% is beneficial. In terms of reducing macrovascular disease, the most worthwhile approach is to target an HbA1c value of less than 7% and begin a multifaceted cardiovascular risk-reduction approach as early as possible.
Footnotes None declared The parties in this debate refute each other’s arguments in rebuttals available at www.cfp.ca. Go to the full text of this article on-line, click on CFPlus in the menu at the top right-hand side of the page. Join the discussion by clicking on Rapid Responses. Cet article se trouve aussi en français à la page 584. References
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