Major findings from the ADVANCE study: glucose-lowering arm



by M. E. Cooper, Australia


Mark E. COOPER, MB, BS,
PhD, FRACP
Diabetes Division, Baker IDI
Heart and Diabetes Institute
Melbourne, Victoria
AUSTRALIA

In the glucose arm of the Action in Diabetes and Vascular disease: PreterAx and DiamicroN Controlled Evaluation (ADVANCE) study, subjects were randomized to either intensified glycemic control (n=5571) involving the use of gliclazide modified release (MR) and other drugs, as required, or to standard management (n=5569). In the intensified glycemic control arm, the strategy was to reduce glucose levels with the aim of reaching a glycated hemoglobin ≤5%. In this group, after maximizing the dose of gliclazide MR, there was sequential addition and/or an increase in the dose of metformin, thiazolidinediones, acarbose, or insulin. At the end of the follow-up, mean HbA1c was 6.5% and 7.3% in the intensive and standard groups, respectively. There was a statistically significant 10% decrease in the primary end point, a composite of micro- and macrovascular complications. This effect on the primary end point appeared to be related predominantly to the 14% decrease in microvascular complications and, in particular, to the reduction in renal, rather than retinal, events. These findings emphasize the role of intensified glycemic control in reducing the major burden of diabetes, its vascular complications. It is anticipated that further follow-up of these subjects over the next few years will allow us to determine if the beneficial effects seen with respect to renal disease ultimately translate into reduced cardiovascular events and a decrease in overall mortality.

Medicographia. 2009;31:232-237 (see French abstract on page 237)

Rationale of the ADVANCE study

Although the link between hyperglycemia and complications has been clearly demonstrated in type 1 diabetes, primarily from the findings of the Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial,1 the issue has remained unresolved with respect to type 2 diabetes. At the time of the design and commencement of the Action in Diabetes and Vascular disease: PreterAx and DiamicroN Controlled Evaluation (ADVANCE) study, the best data available came from the United Kingdom Prospective Diabetes Study (UKPDS), which demonstrated that intensified glycemic control with various drugs, including sulphonylureas and insulin (achieving a reduction in HbA1c of 0.9% when compared with conventional treatment in newly diagnosed type 2 diabetic subjects), led to reduced microvascular complications.2 With an achieved average HbA1c of 7% in UKPDS, there was a tendency towards, but neither a statistically significant decrease in macrovascular events nor a decrease in mortality. These findings led to most, but not all, international guidelines to suggest an HbA1c of _6.5% or 7% as the appropriate target for glucose-lowering treatment in type 2 diabetes.3,4

Design of the ADVANCE study

The ADVANCE study has made great progress in helping us to determine what is the right approach for managing hyperglycemia in type 2 diabetes. The ADVANCE study was an investigator- initiated multinational trial. Within the glucose arm of the study, subjects were randomized to either intensified glycemic control (n=5571) involving the use of gliclazide modified release (MR) and other drugs, as required, or to standard management (n=5569). In the intensified glycemic control arm, the strategy was to reduce glucose levels with the aim of reaching a glycated hemoglobin ≤6.5%. In this group, after maximizing the dose of gliclazide MR, there was sequential addition and/or an increase in the dose of metformin, thiazolidinediones, acarbose, or insulin. The intensified glycemic control group also had more frequent follow-up visits and were encouraged to be more active with respect to home blood-glucose monitoring. All analyses in this trial were based on the intention to treat principle.

Results of the ADVANCE study

The median duration of follow-up was 5 years, and, at baseline, both groups had similar characteristics, including a baseline HbA1c of 7.5%. At the end of the follow-up, mean HbA1c was 6.5% and 7.3% in the intensive and standard groups, respectively (Figure 1). In terms of the various glucose- lowering treatments, the intensive group were taking more drugs, and, in particular in this group, insulin was prescribed in over 40% of subjects versus 24% in the standard group. The glucose arm of the study achieved its primary end point, a statistically significant 10% decrease in a composite of micro- and macrovascular complications.5 There was no evidence of an interaction between the blood pressure and glucose interventions for this primary outcome. This effect on the primary end point appeared to be related predominantly to the 14% decrease in microvascular complications and, in particular, to the 21% reduction in renal, rather than the nonsignificant 5% decrease in retinal, events. There was no significant effect on major macrovascular events, including no statistical decrease in cardiovascular mortality. Importantly, there was no evidence of an increase in total mortality. Indeed, there was a nonstatistical 7% decrease in mortality. No effects were seen on nonfatal myocardial infarction or stroke.

Figure 1
Figure 1. Glucose control at baseline and during follow-up, according to glucose-control strategy.
Data are shown for mean glycated hemoglobin. The average difference between the intensive-control group and the standard-control group for the follow-up period was 0.67 percentage points (95% confidence interval [CI], 0.64 to 0.70) for glycated hemoglobin.
Reproduced from reference 5: Patel A, MacMahon S, Chalmers J, et al. N Engl J Med. 2008;358:2560-2572. Copyright © 2008, Massachusetts Medical Society.

Clinical relevance of the findings of the ADVANCE study

The major issue is the clinical relevance of these findings and how these will translate into routine care of type 2 diabetes. The population studied came from 20 different countries of diverse ethnic backgrounds, with a significant proportion of subjects from Asia. Furthermore, when one looks at the demographic characteristics of the individuals in this study, these reflect the clinical features of type 2 diabetic subjects currently managed throughout the world. Indeed, if one compares the age, gender, glycemic control, and blood pressure of the subjects in the ADVANCE study, their clinical characteristics are almost identical to those from recently reported studies of the French and Australian type 2 diabetic populations.6,7 Thus, the conclusions from the ADVANCE study should be considered highly relevant for both specialists and family practitioners who treat type 2 diabetes.

Renal events in the glucose arm of the ADVANCE study

One of the most important findings from the ADVANCE study was the demonstration of reduced renal events in the inten- sified glucose control arm (Figure 2).5 Renal disease is itself a major cause of morbidity and mortality in the diabetic population. Furthermore, in Western countries, diabetic nephropathy remains the major cause of end-stage renal disease (ESRD), with diabetes being the primary cause of renal failure in over 50% of individuals currently entering renal replacement programs.8 There was also a reduction in new-onset microand macroalbuminuria with intensified glycemic control. This will clearly ultimately translate into reduced ESRD, and although in the ADVANCE study there was a greater than 30% decrease in the development of ESRD, this did not reach statistical significance since only a small number of subjects developed this very serious diabetic complication.

Figure 2
Figure 2. Relative effects of glucose-control strategy on all prespecified primary and secondary outcomes. The diamonds incorporate the point estimates, represented by the vertical dashed lines, and the 95% confidence intervals of the overall effects within categories; for subcategories, black squares represent point estimates (with the area of the square proportional to the number of events), and horizontal lines represent 95% confidence intervals. The hazard ratios and relative risk reductions are given for intensive glucose control as compared with standard glucose control.
Reproduced from reference 5: Patel A, MacMahon S, Chalmers J, et al. N Engl J Med. 2008;358:2560-2572. Copyright © 2008, Massachusetts Medical Society.

Renal and cardiovascular end points in the ADVANCE study

It is well known that there is a close association between renal and cardiovascular disease in diabetes and that both micro- and macroalbuminuria have been reported to be linked to the subsequent development of macrovascular disease. Indeed, this association was also observed in the ADVANCE study population when assessing the link between microand macroalbuminuria at baseline and in the subsequent development not only of renal, but also of cardiovascular events. Thus, although the ADVANCE study did not demonstrate a decrease in cardiovascular mortality or events over the relatively short period of 5 years, one cannot exclude the pos- sibility that longer follow-up would demonstrate a benefit on macrovascular disease. There are such precedents in the literature, including, firstly, the recent report on the longer follow- up of the UKPDS cohort, where the initial borderline benefit seen with intensified glycemic control on cardiovascular disease has now been shown to be very clear after a much longer period of follow-up, despite subjects returning back to usual care without ongoing, intensified, glucose-lowering management.9 Secondly, in the Steno 2 study, where multifactorial intervention with not only intensified glycemic control, but also active treatment with antihypertensive and lipidlowering therapy was included, the initial evaluation after 4 years of active treatment revealed no evidence of a decrease in macrovascular, but a reduction in microvascular, events.10 However, at the 8-year time point, there was a decrease in macrovascular disease11 that, interestingly, translated into a decrease in mortality 5 years later, despite subjects returning to usual care after 8 years in the study.12 These findings emphasize the importance of either ongoing follow-up of subjects in these relatively short duration clinical trials involving cardiovascular end points or considering trials which involve active interventions for more than 5 years. Thus, it is critical to continue to monitor cardiovascular events and mortality in the subjects from the ADVANCE study, as is planned.

ADVANCE findings with respect to those from the ACCORD study

The findings of the ADVANCE study need to be considered in the light of the results of the Action to Control CardiOvascular Risk in Diabetes (ACCORD) study,13 published at the same time, as well as the as the more recently reported findings of the smaller Veterans Affairs Diabetes Trial (VADT) study.14,15 The ACCORD study also included more than 10 000 type 2 diabetic subjects, although all subjects in that study were recruited from the US and Canada.13 The glucose arm of that trial was prematurely terminated due to an unexpected 22% increase in total mortality, primarily reflecting the reported increase in cardiovascular mortality in that study. This increase in mortality remains unexplained, but was clearly not observed in the ADVANCE study. Furthermore, as yet, the results on microvascular events have not been reported from the ACCORD trial.

There are a number of key differences between the ACCORD and ADVANCE studies. In the ACCORD study, subjects had a higher baseline HbA1c, a higher body mass index (BMI), and lower blood pressure than in the ADVANCE study. Thus, the investigators from the ADVANCE study have explored whether subjects with higher baseline HbA1c, BMI >30, and lower blood pressure behaved differently to the other subjects in terms of response to intensified glycemic control. However, even in the subjects from the ADVANCE trial that matched the ACCORD cohort more closely, no evidence of increased cardiovascular or total mortality was observed, nor did these individuals behave differently in terms of their clinical response to more intensive glucose-lowering management.5

In the ACCORD study, the intensive glucose-lowering strategy was a much more aggressive approach with reductions in HbA1c of between 1% and 1.5% achieved within 6 months of starting active treatment.13 Multiple drugs were used with many subjects on up to 4 glucose-lowering drugs within the first year of the study. Indeed, a very high proportion of the intensified glucose control group in that study ended up on treatment with the thiazolidinedione rosiglitazone and/or insulin. This approach clearly comes at a price—increased hypoglycemia and weight gain. In the ADVANCE study, the glucose- lowering strategy was much more gradual than in the ACCORD trial, with the maximal HbA1c reduction not seen till at least 2 to 3 years after the commencement of the ADVANCE study. This approach was not associated with significant weight gain, and the rates of hypoglycemia were much lower than observed in the ACCORD study. Although the ACCORD investigators have suggested that the marked increase in hypoglycemia does not explain the increase in mortality seen with aggressive glucose-lowering in that study,13 one cannot be sure as to the impact of intermittent, often unrecognized hypoglycemia in diabetic subjects with silent cardiovascular disease. Clearly, this is a potential area of exciting research, and, in particular, the link between hypoglycemia (including asymptomatic episodes), the sympathetic nervous system, and cardiovascular events needs further examination.16

Tissue remodeling in diabetes

As outlined previously, the ADVANCE study did not demonstrate a decrease in cardiovascular disease, although there appears to be a trend, albeit modest and not statistically significant after 5 years of treatment.5 It remains unexplained as to why no statistically significant beneficial effect was observed on macrovascular disease in this study. This may not only relate to the short duration of the study, but could reflect underlying pathological processes within the diabetic vasculature. Indeed, in the seminal studies involving pancreatic transplantation in type 1 diabetes, renal morphological injury took up to 10 years to reverse, despite a decade of normoglycemia.17 The rates of remodeling within organs, such as the kidney, and within blood vessels may be rather slow and, thus, take many years of improved glycemic control for endorgan injury to be reversed.

Advanced glycation

One of the key biochemical mechanisms implicated in diabetic complications, a result of chronic hyperglycemia, is known as advanced glycation.18 In blood vessels, these advanced glycation end products (AGEs) accumulate and may persist, despite improved glycemic control. These chemical moieties interact with specific receptors, such as the receptor for advanced glycation end products (RAGE), to induce vascular inflammation and promote atherosclerosis.19 Thus, it may be necessary to not only reduce glucose levels, but to directly inhibit the advanced glycation pathway. Such an approach is currently under active clinical investigation, with preclinical studies in models of diabetic complications providing promising results.20,21 It should also be noted that angiotensin-converting enzyme inhibitors, such as perindopril, can directly influence various components of the AGE/RAGE pathway22 and could explain the added benefits seen in the subjects from the intensive glycemic control group in ADVANCE, who also had more aggressive antihypertensive treatment with a perindopril- based regimen.

Hyperglycemic memory

Another possibility for the lack of dramatic effect of glucose lowering on macrovascular disease may relate to a phenomenon known as “hyperglycemic memory”. It has previously been reported in type 1 diabetes in the DCCT/EDIC studies and more recently in type 2 diabetes in the longer term follow-up of UKPDS that there are sustained effects on the vasculature as a result of prior levels of metabolic control.1,9 For example, in both the DCCT/EDIC and UKPDS studies, despite subjects returning to usual management of their hyperglycemia, these individuals continued to benefit from their previous period of better metabolic control.1,9 The underlying explanation for this phenomenon, known as either “hyperglycemic memory” or the “legacy effect,” remains unexplained,23 but recently it has been suggested that epigenetic mechanisms may be involved,24,25 possibly with reactive oxygen species acting as key intermediates.24,26 This is likely to be an active area of ongoing research with the molecular mechanisms responsible for conferring hyperglycemic memory being increasingly delineated.

Summary

ADVANCE provides us with new evidence emphasizing the role of intensive glucose control in reducing diabetic complications, in particular, nephropathy. Thus, the current guidelines suggesting that clinicians should aim to achieve an HbA1c of 6.5% or 7% appear sensible and can be justified by the more recent data obtained from trials like ADVANCE5 and the recent long-term follow-up from UKPDS.9 The practical and gentle strategy of reducing glucose levels in order to achieve, on average, an HbA1c of 6.5%, using regimens involving agents such as gliclazide as first-line therapy with subsequent use of other oral agents and, ultimately, often insulin, appears to be feasible, as has been demonstrated in a typical group of type 2 diabetic subjects in ADVANCE. This strategy, of course, must be considered in conjunction with important lifestyle measures, including diet (often with an emphasis on weight loss) as well as increased exercise. Such individuals could be managed in general or specialist practice, and it is likely that this strategy will not be associated with major side effects, such as severe hypoglycemia or excessive weight gain.

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