Intensive risk factor management: long-term benefits of earlier intensive glucose control in type 2 diabetes

The George Institute for Global
Health, University of Sydney
School of Public Health and
Preventive Medicine, Monash
University, Melbourne

Intensive risk factor
management: long-term
benefits of earlier intensive
glucose control in
type 2 diabetes


by S. Zoungas , Australia

In the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial, intensive glucose control (targeting HbA1c ≤6.5%) reduced the risk of nephropathy compared to standard glucose control in patients with type 2 diabetes. The posttrial follow-up (ADVANCEON [ObservatioNal study]) examined whether in-trial effects were sustained or new long-term benefits emerged for major outcomes. The primary end points were death from any cause and major macrovascular events. Secondary end points included major clinical microvascular events and requirement for renal replacement therapy. Of 11 140 patients originally randomized, 8494 were followed posttrial for a median of 5.4 years. In-trial differences in mean HbA1c levels between treatment groups were lost by the first postrandomization visit after 2.9 years. No reduction was evident in cumulative risk of death from any cause (hazard ratio [HR] for intensive versus standard control, 1.00; 95% confidence interval [CI], 0.92-1.08), major macrovascular events (HR, 1.00; 95% CI, 0.92-1.08), or major clinical microvascular events (HR, 0.92; 95% CI, 0.80- 1.05). By contrast, cumulative risk of end-stage kidney disease (ESKD) was significantly reduced in the intensive group (HR, 0.54; 95% CI, 0.34-0.85). Posttrial follow-up provided no evidence that in-trial differences in glucose control produced long-term mortality or major macrovascular events benefits. However, significant in-trial ESKD benefits were still evident, highlighting the importance of glucose control for renal protection.

Medicographia. 2016;38:45-48 (see French abstract on page 48)

Posttrial follow-up studies of patients with diabetes have previously reported long-term beneficial effects of earlier periods of intensive glucose control on a range of outcomes, including mortality and macrovascular events.1,2 The Epidemiology of Diabetes Intervention and Complications (EDIC) study extension of the Diabetes Control and Complications Trial (DCCT) in young patients with type 1 diabetes with no history of cardiovascular disease, hypertension, or hypercholesterolemia reported a lower risk of macrovascular events, as well as sustained benefit for microvascular complications beyond the period of randomized treatment.1 The postintervention follow-up of the United Kingdom Prospective Diabetes Study (UKPDS) also reported long-term beneficial effects of intensive glucose control in patients with newly diagnosed type 2 diabetes.2 In patients formerly assigned to intensive therapy, the reduced risk of microvascular events was maintained and previously nonsignificant estimates of effect on death and myocardial infarction became significant compared with patients on conventional therapy, with extended follow- up.2 These long-term benefits were ascribed to a metabolic memory or legacy effect of prior intensive glucose lowering.3-6 The ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN Mr Controlled Evaluation) trial assessed the effects of intensive glucose control versus standard glucose control in a broad cross-section of patients with type 2 diabetes.7 Intensive glucose control was associated with a reduction in risk of the composite primary outcome of major macrovascular and microvascular events, primarily due to a clear reduction in new or worsening nephropathy.7 This included a reduction in the need for renal replacement therapy.8 The trial identified no clear protective or harmful effects of intensive glucose control on all-cause death or major macrovascular events.7 The posttrial follow-up of ADVANCE, ADVANCE- ON (ObservatioNal study), investigated whether the in-trial intensive glucose control produced long-term benefits after completion of randomized treatment.


ADVANCE-ON was a posttrial follow-up study of all surviving ADVANCE patients. The recruitment of patients, study design, and detailed methods for the ADVANCE trial have previously been published.9 In brief, 11 140 individuals with type 2 diabetes aged 55 years or older with at least one additional risk factor for cardiovascular disease were enrolled from 215 centers in 20 countries between 2001 and 2003.

Patients were randomly assigned to: (i) a gliclazide modified release (Mr)–based intensive glucose control regimen, aiming for a glycated hemoglobin (HbA1c) level of 6.5% or lower, or to standard glucose control based on local guidelines of participating countries; and (ii) to a single-pill (fixed-dose) combination of perindopril and indapamide (4 mg/1.25 mg) or matching placebo, after a 6-week active run-in period.

The last ADVANCE trial visits for the blood glucose control comparison were completed in January 2008, after a median follow-up period of 5.0 years. At this time, patients ceased the randomized interventions and returned to the usual care of their treating physician.

Posttrial follow-up and assessments
All local ADVANCE trial sites were invited to participate in ADVANCE-ON and 172 of 215 (80%) agreed. In April 2010, annual posttrial visits commenced. A random subset of 2000 patients, balanced across regions and across the prior randomized treatment arms, was also invited to undergo assessment of HbA1c, fasting blood glucose, blood pressure, weight, serum creatinine, and urinary albumin:creatinine ratio at the first posttrial visit.

Study outcomes
The two prespecified primary outcomes for ADVANCE-ON were death from any cause and major macrovascular events (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from any cardiovascular cause). The major microvascular event outcome, as defined in the ADVANCE trial, could not be evaluated in ADVANCE-ON as assessment of serum creatinine and albuminuria were only performed in a subgroup of participants. Consequently, the prespecified secondary outcome for ADVANCE-ON was major clinical microvascular events, defined as a composite of requirement for renal replacement therapy, death from renal disease, and severe diabetes-related eye disease (requirement for retinal photocoagulation or diabetes-related blindness in either eye). Other secondary outcomes included the separate components of this outcome and death from any cardiovascular cause, fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, and major hypoglycemia.


As reported, 8494 patients (84%) entered posttrial follow-up and 5131 completed a visit during the final year of the study. The median in-trial, posttrial, and total follow-ups were 5.0 years, 5.4 years, and 9.9 years, respectively. The first posttrial visit occurred a median of 2.9 years after the final ADVANCE trial visit.10

Patient characteristics
The prerandomization characteristics of the ADVANCE trial patients who were enrolled in ADVANCE-ON were broadly similar, according to original treatment assignment, to those of the entire ADVANCE trial cohort.10 A slightly lower prevalence of established vascular disease in the ADVANCE-ON cohort was consistent with a healthy survivor effect.

Treatment patterns
Posttrial use of insulin therapy initially decreased, but then increased in the intensive group and steadily increased in the standard group. In contrast, posttrial use of gliclazide Mr decreased in the intensive group, whilst the use of other sulfonylureas decreased in the standard group. Use of other glucose- lowering therapies, such as gliptins and glucagon-like peptide 1 analogues, increased in both groups. There were no substantive posttrial differences between the original randomized groups in the use of metformin, thiazolidinediones, and α-glucosidase inhibitors.

Figure 1
Figure 1. Cumulative incidence of death from any cause, major
macrovascular events, and end-stage kidney disease, according to
glucose-control group.

This figure shows the percentage of patients who had events at any time after
randomized treatment was started, according to glucose-control group (intensive
or standard). Hazard ratios (intensive versus standard) and P values are shown
for the 10-year period from the start of randomized treatment to the end of the
posttrial follow-up. No significant difference between the intensive and standard
glucose-control groups was found for death from any cause (panel A) or major
macrovascular events (panel B), but a significant difference in end-stage kidney
disease was observed (panel C). For the reader’s benefit, the panel C inset shows
data on an enlarged y axis
Modified from reference 10: Zoungas et al; ADVANCE-ON Collaborative Group.
N Engl J Med. 2014;371(15):1392-1406. © 2014, Massachusetts Medical Society.

HbA1c differences
The mean in-trial difference in HbA1c (0.67%; 95% confidence interval [CI] 0.64% to 0.70%) at the end of randomized therapy 7 was lost by the first posttrial visit (0.08%; 95% CI, -0.07% to 0.22%), with a rise in HbA1c in the intensive control group approaching that observed in the standard control group.10 HbA1c levels in the two groups remained similar at the conclusion of posttrial follow-up (7.2% vs 7.4%).10

Primary and secondary outcomes
Consistent with in-trial findings, there were no cumulative benefits of intensive glucose control for either death from any cause or major macrovascular events (Figure 1).10 There was also no evidence that the cumulative effects on death from any cause varied between the patient subgroups studied (all P>0.1).10 In addition, there were no cumulative benefits for major clinical microvascular events or severe diabetes-related eye disease considered separately.10 However, there was a highly significant cumulative benefit across the overall intrial and posttrial period for end-stage kidney disease (hazard ratio [Hr] for requirement for renal replacement therapy, 0.54; 95% CI, 0.34-0.85) (Figure 1).10 No beneficial effects emerged during the posttrial period for any other secondary outcome. There was no interaction between the effects of glucose control and BP lowering for any primary or secondary outcome (all P for interaction >0.1).1010


After a total of 10 years of in-trial and posttrial follow up of the ADVANCE cohort, no long-term benefits for mortality or macrovascular events were observed. However, the large benefit for end-stage kidney disease observed in-trial was sustained. In ADVANCE, clear benefits of intensive glucose control were primarily due to reductions in new or worsening nephropathy, driven by reductions in progression of albuminuria and the “hard” clinical outcome of end-stage kidney disease requir-ing renal replacement therapy. In ADVANCE-ON, persisting benefits for this “hard” clinical outcome were observed. If persistence of in-trial benefits during the posttrial period constitutes a metabolic memory or legacy effect, then we had this in ADVANCE-ON for end-stage kidney disease.

Our findings differ from the DCCT-EDIC and UKPDS posttrial follow-up studies.1,2 Both of these trials reported the emergence of long-term beneficial effects of earlier periods of intensive glucose control on major macrovascular events and/or mortality.1,2 It is possible that there were physiological differences in response to glucose lowering across the trial populations in DCCT-EDIC, UKPDS, and ADVANCE. First, the younger patients with type 1 diabetes (DCCT-EDIC)1 or newly diagnosed type 2 diabetes (UKPDS)2 may have been more likely to achieve long-term benefits from glucose lowering than older patients with established disease included in ADVANCE. Second, there were differences between the studies in terms of in-trial exposure to HbA1c, which differed by only 0.7% over 5 years in ADVANCE, but was much larger in the DCCT (Δ HbA1c was 2.0% over a mean follow-up of 6.5 years) and slightly larger in the UKPDS (Δ HbA1c was 0.9% over a median follow-up of 10 years).1,2,8 Baseline HbA1c levels of patients were also much higher in the DCCT and UKPDS (both >8.5%) than in ADVANCE (7.5%).1,2,7 Third, more widespread use of better background preventive therapy in ADVANCE may have masked any long-term beneficial effects on mortality and cardiovascular events.


Intensive glucose control is important for preventing serious renal complications and does not cause harm, ie, does not increase risk of mortality or cardiovascular events, in people with longstanding type 2 diabetes.

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3. Chalmers J, Cooper M. The UKPDS and legacy effects. N Engl J Med. 2008; 359(15):1618-1620.
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6. Pirola l, Balcerczyk A, Okabe J, El-Osta A. Epigenetic phenomena linked to diabetic complications. Nat Rev Endocrinol. 2010;6(12):665-675.
7. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
8. Perkovic V, Heerspink Hl, Chalmers J, et al; ADVANCE Collaborative Group. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int. 2013;83(3):517-523.
9. ADVANCE Management Committee. Study rationale and design of ADVANCE: action in diabetes and vascular disease – Preterax and Diamicron Mr controlled evaluation. Diabetologia. 2001;44(9):1118-1120.
10. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow- up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371(15):1392-1406.

Keywords: ADVANCE-ON; end-stage kidney disease; gliclazide; intensive glucose control; legacy effect; metabolic memory; type 2 diabetes