ADVANCE-ON*: current status

Sophia ZOUNGAS1,2,MD, PhD


1. The George Institute for Global Health, University of Sydney, Sydney
and 2. School of Public Health and Preventive Medicine
Monash University – Melbourne, AUSTRALIA

ADVANCE-ON*: current status

*Action in Diabetes and Vascular disease PreterAx and DiamicroN MR Controlled Evaluation posttrial ObservatioNal study

by S. Zoungas and J. Chalmers, Australia

ADVANCE-ON [Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation posttrial ObservatioNal study] aims to determine the posttrial effects of the two interventions studied in ADVANCE: (i) the glucose-lowering intervention (intensive gliclazide MR– based versus standard guideline–based therapy) and (ii) the blood pressure– lowering intervention (routine therapy with perindopril-indapamide versus placebo) in individuals with type 2 diabetes. ADVANCE-ON will clarify and quantify the long-term(often referred to as legacy) effects of these two interventions in a broader population of patients at high risk of cardiovascular events, from high- and low-to-middle–income countries, and in the setting of comprehensive risk factor management. The conclusions of this follow-up study are expected to have profound clinical implications for the care of patients with type 2 diabetes around the world.

Medicographia. 2013;35:61-66 (see French abstract on page 66)

Rationale for ADVANCE-ON

_ Intensive glucose lowering
Epidemiological studies have previously demonstrated an important relationship between the level of glycemic control and risks of macrovascular and microvascular complications in people with type 2 diabetes. In patients with newly diagnosed type 2 diabetes in the UKPDS (United Kingdom Prospective Diabetes Study), tight glucose control (achieved HbA1c: 7%) led to significant reductions in the risk of microvascular events,1 a trend toward a reduction in myocardial infarction, and significant reduction in macrovascular events in the subgroup of patients allocated to metformin treatment.2 These data suggested that a strategy to intensively lower glucose in all patients with type 2 diabetes might reduce such outcomes. However, a reduction in macrovascular events has not been confirmed in recent large-scale clinical trials with intensive glucose lowering (achieved HbA1c range: 6.4% to 6.9%) in patients of long-standing type 2 diabetes (ADVANCE [Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation], ACCORD [Action to Control CardiOvascular Risk in Diabetes], and VADT [Veterans Affairs Diabetes Trial]).3-5

In the glucose-control comparison of the ADVANCE trial after a mean follow-up period of 4.8 years,4 intensive glucose lowering based on gliclazide MR (modified release) and other glucose-lowering therapies added to achieve a mean HbA1c of 6.5% (versus 7.3% in the standard glucose control group) was associated with a reduced risk of major macrovascular or microvascular events (hazard ratio [HR] 0.90; 95% confidence interval [CI], 0.82-0.98; P=0.01) (Figure 1A).4 There was a separate reduction in major microvascular events (HR 0.86; 95%CI, 0.76-0.98; P=0.02) (Figure 1A), primarily due to a reduction in the incidence of nephropathy (HR 0.79; 95% CI, 0.66-0.93; P=0.006) with no significant effect on retinopathy. In addition, the risks of major macrovascular events, death from cardiovascular cause, and death from any cause were not significantly reduced (macrovascular events: 0.94; 95%CI, 0.84-1.06; P=0.32; death from cardiovascular cause: 0.88; 95%CI, 0.74-1.04; P=0.12; death from any cause: 0.93; 95% CI, 0.83-1.06; P=0.28) (Figure 1A and 1B). For each of these outcomes, the 95%CIs of the point estimate included a HR consistent with modest, but potentially important clinical benefits.

Figure 1
Figure 1.
Effects of intensive glucose lowering with a gliclazide MR–based regimen on A) major
macrovascular events, major microvascular events, and B) death.

Abbreviation: CI, confidence interval.
After reference 4: ADVANCE Collaborative Group et al.

N Engl J Med. 2008; 358(24):2560-2572. © 2008, Massachusetts Medical Society.

In contrast, the ACCORD trial and the VADT reported no significant effects of intensive versus standard glucose control on macrovascular events (ACCORD and VADT) or microvascular events (VADT).3,5 In fact, the ACCORD trial, which targeted an HbA1c level of less than 6%and was conducted in a different population in North America, reported an increase in the risk of mortality with intensive versus standard glucose control and questioned the safety of intensive glucose lowering in older patients with diabetes of longer duration and with existing cardiovascular complications.3

_ Long-term posttrial effects of intensive glucose lowering
The DCCT/EDIC (Diabetes Intervention and Complications Trial/Epidemiology of Diabetes Interventions and Complications) study in patients with type 1 diabetes and no history of cardiovascular disease, hypertension, or hypercholesterolemia was the first to report the long-term beneficial effects of intensive glucose control on a range of vascular outcomes in the EDIC study.6 In this posttrial observational study, patients formerly assigned to intensive insulin therapy as compared with those assigned to conventional insulin therapy had a lower risk of macrovascular events as well as a sustained benefit as regards microvascular complications beyond the period of randomized treatment. This was achieved despite loss of between-group differences in glycemic control as patients in the conventional insulin therapy group were offered intensive insulin therapy for the duration of the posttrial observation period. Intensive insulin therapy was also associated with a reduced risk of incident hypertension during posttrial follow up.7 These long-term benefits were ascribed to a “metabolic memory” effect, introducing the paradigm of the legacy effect of intensive glucose lowering.

More recently, the post intervention follow-up of the UKPDS also demonstrated the long-term beneficial effects of intensive glucose control on macrovascular and microvascular events in patients with newly diagnosed type 2 diabetes at study entry.8 In patients formerly assigned to intensive therapy (either sulfonylurea or insulin) compared with those formerly assigned to conventional therapy (diet alone), the reduced risk of microvascular events was maintained and a reduced risk of death from any cause and of myocardial infarction emerged with posttrial follow-up. This was achieved despite an early loss of between-group differences in glycemic control as no attempt was made to continue previously assigned therapies.

The mechanisms responsible for the legacy effect of intensive glucose lowering remain unclear. Some postulate that the long-term vascular effects of hyperglycemia may be mediated by accumulation of advanced glycation end products in the vasculature. It is therefore speculated that in the UKPDS and the DCCT/EDIC studies the earlier periods of tighter glucose control resulted in less accumulation of advanced glycation end products and emergent long-term protection from cardiovascular disease.6,9 Alternatively, the earlier tight glucose control may have reduced the development of microvascular renal disease, a well-recognized risk factor for cardiovascular disease. This may translate into longer-term cardiovascular benefits for those treated intensively.6,9 Such a reduction in microvascular renal disease has previously been reported by the DCCT and the UKPDS.1,10 However, it remains uncertain as to whether any persisting or emerging long-term benefits of prior intensive glucose control will be observed in patients such as those in ADVANCE, which in comparison with those in the UKPDS were enrolled from a diverse range of countries from around the world, had longer disease duration with a mean of 8.3 years at baseline, and prevalent macrovascular disease at study entry in about one-third of the patients.

Figure 2
Figure 2. Effects of perindopril-indapamide on major macrovascular and major microvascular events.

Abbreviations: CI, confidence interval; Ind, indapamide;
Per, perindopril.
After reference 18: Patel et al.
Lancet. 2007;370(9590):829-840. © 2007,
Elsevier Ltd.

_ Blood pressure lowering
Among patients with type 2 diabetes, blood pressure is a particularly important determinant of cardiovascular disease risk.11,12 As reported by previous studies, this relationship is continuous and of similar strength among those with or without diabetes.13,14 In the UKPDS, systolic blood pressure levels were linearly associated with the risks of myocardial infarction and microvascular events.15 Additionally, in the Prospective Studies Collaboration, the association between systolic blood pressure and death was age dependent in those with diabetes with greater risks observed at younger age.16 A number of randomized clinical trials have previously demonstrated the cardiovascular benefits of treating hypertensive patients who have type 2 diabetes. In a meta-analysis of blood pressure– lowering therapy, the effects of treatment were similar among those with and those without diabetes.17 Recently, the ADVANCE trial has extended these findings by demonstrating the benefits of routine blood pressure lowering, irrespective of initial blood pressure levels, in a group of patients with established type 2 diabetes and who were at high vascular risk and receiving comprehensive preventive medical care.18

In the blood pressure–lowering comparison of the ADVANCE trial after a mean follow-up period of 4.3 years,18 routine treatment with perindopril-indapamide versus placebo resulted in a mean reduction in systolic and diastolic blood pressure of 5.6 mm Hg and 2.2 mm Hg, respectively, and was associated with a reduced risk of major macrovascular or microvascular events (HR 0.91; 95% CI, 0.83-1.00; P=0.04). The separate reductions in macrovascular and microvascular events were similar, but not independently significant (macrovascular: 0.92; 95% CI, 0.81-1.04; P=0.16; microvascular: 0.91; 95%CI, 0.80-1.04; P=0.16) (Figure 2).18 The risk of death from any cause was reduced by 14% (HR 0.86; 95% CI, 0.75- 0.98; P=0.03) and the risk of death from cardiovascular disease was reduced by 18% (HR 0.82; 95% CI, 0.68-0.98; P=0.03). There were also significant reductions in total coronary (HR 0.86; 95% CI, 0.76-0.98; P=0.02) and total renal events (HR 0.79; 95% CI, 0.73-0.85; P<0.0001). The reduction in renal events was largely attributable to a significant reduction in the development of microalbuminuria. Moreover, the benefits observed appeared independent of ancillary treatments at baseline and of the presence or absence of hypertension at study entry.

Table I
Table I. Comparison of the baseline participant characteristics in ADVANCE and

Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation.
ADVANCE-ON, ADVANCE posttrial ObservatioNal study; HbA1c, glycated hemoglobin; IQR,
interquartile range; n, number; SD, standard deviation.

_ Long-term posttrial effects of blood pressure lowering
Although the vascular benefits of intensively treating blood pressure in type 2 diabetes are widely accepted, persistent posttrial effects continue to be debated. In the 10-year posttrial observational follow-up of the blood pressure–lowering arm of the UKPDS, the benefits of tight blood pressure control on death, stroke, and microvascular disease were not maintained with early loss of between-group differences in blood pressure.19 This was attributed to the rapid “on and off effects” of blood pressure treatment as well as the drop in blood pressure levels observed in the less-tight control group during follow-up.19 Yet the significantly worse glycemic control in the tight versus less-tight blood pressure control group may have masked a longer-term effect. In contrast, the HOPETOO (Heart Outcomes Prevention Evaluation–The Ongoing Outcomes) study extension, which included patients with vascular disease and/or diabetes, demonstrated several years of persistent cardiovascular benefits after completion of in-trial randomized blood pressure–lowering treatment and prolonged observational follow-up.20 This was achieved despite mean blood pressure being similar in the randomized groups at the end of the 2.6 years of extended follow-up. In addition, the 2-year extended follow-up of the Syst-Eur trial (Systolic Hypertension in Europe) on blood pressure–lowering therapy in older patients with systolic hypertension has also reported maintained benefits of immediate as compared with delayed post randomization open-label treatment of elevated blood pressure.21 Moreover, the relative risk reductions achieved with additional follow-up could only be explained by former allocation to active treatment, as the rate of cardiovascular events in those assigned to active treatment was similar to those assigned placebo.21 Whether these benefits would persist with the longer period of posttrial follow-up proposed by ADVANCE-ON (ADVANCE posttrial ObservatioNal study) remains to be seen.

ADVANCE-ON: progress

The last visits in the ADVANCE trial were completed at the end of January 2008. Phase 1 of the study will follow participants for up to 6 years after completion of randomized intervention (funded) and phase 2 will follow participants for up to 10 years (subject to funding).

All 10 063 surviving ADVANCE trial patients who returned to the care of their usual physicians after ceasing the randomized interventions were invited to participate in ADVANCE-ON. A random sample of patients was selected for repeat measurement of HbA1c and blood pressure levels.

By mid-May 2012, 8194 patients (mean age 76 years, 43%female) had completed the first posttrial visit (22% Australasia, 38% China, 4% Canada, 16% Continental Europe, and 20% Northern Europe). Of these patients, 622 had died and 1413 had provided repeat HbA1c and blood pressure measurements. A comparison of the baseline characteristics of the ADVANCE and ADVANCE-ON participants is provided in Table I.

At that time, the mean HbA1c levels of the original intensive and standard glucose control groups were 7.25%and 7.30%, respectively, and the mean blood pressure level in both the original perindopril-indapamide and placebo groups was 137/ 75 mm Hg. While treatment with glucose-lowering drugs had converged, 36% of those in the original intensive glucose control group were still taking insulin compared with 31% in the standard group.


The ADVANCE-ON cohort is representative of the original ADVANCE population. As expected, early after completion of the ADVANCE trial and cessation of the randomized interventions, the patterns of glucose and blood pressure control in the treatment groups converged. Recruitment and data collection are ongoing to ensure all posttrial patient outcomes are captured.

Acknowledgements: ADVANCE-ON is partially funded by an unrestricted educational grant from Servier International and a project grant from the National Health and Medical Research Council of Australia (NHMRC) (ID 1006367). The study was initiated and designed by the investigators, independently of Servier and the NHMRC, and the data will be collected, analyzed and published independently of Servier.

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2. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-865.
3. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.
4. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
5. DuckworthW, Abraira C,Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360(2):129-139.
6. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-2653.
7. de Boer IH, Kestenbaum B, Rue TC, et al; Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Insulin therapy, hyperglycemia, and hypertension in type 1 diabetes mellitus. Arch Intern Med. 2008;168(17):1867-1873.
8. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577- 1589.
9. Chalmers J, Cooper ME. UKPDS and the legacy effect. N Engl J Med. 2008; 359(15):1618-1620.
10. The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 1995;47(6):1703- 1720.
11. Kuller LH, Velentgas P, Barzilay J, Beauchamp NJ, O’Leary DH, Savage PJ. Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality. Arterioscler Thromb Vasc Biol. 2000;20(3):823-829.
12. Stamler J, Dyer AR, Shekelle RB, Neaton J, Stamler R. Relationship of baseline major risk factors to coronary and all-cause mortality, and to longevity: findings from long-term follow-up of Chicago cohorts. Cardiology. 1993;82(2-3): 191-222.
13. Lawes CM, Rodgers A, Bennett DA, et al; Asia Pacific Cohort Studies Collaboration. Blood pressure and cardiovascular disease in the Asia Pacific region. J Hypertens. 2003;21(4):707-716.
14. Asia Pacific Cohort Studies Collaboration; Kengne AP, Patel A, Barzi F, et al. Systolic blood pressure, diabetes and the risk of cardiovascular diseases in the Asia-Pacific region. J Hypertens. 2007;25(6):1205-1213.
15. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321(7258):412-419.
16. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903-1913.
17. Turnbull F, Neal B, Algert C, et al; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005;165(12):1410-1419.
18. Patel A; ADVANCE Collaborative Group; MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829-840.
19. Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med. 2008;359 (15):1565-1576.
20. Bosch J, Lonn E, Pogue J, Arnold JM, Dagenais GR, Yusuf S; HOPE/HOPETOO Study Investigators. Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension. Circulation. 2005;112 (9):1339-1346.
21. Staessen JA, Thijs L, Fagard R, et al; Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial. J Hypertens. 2004; 22(4):847-857.

Keywords: ADVANCE-ON; blood pressure lowering; HbA1c; intensive glucose lowering; long-term posttrial effect; type 2 diabetes