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1 May 2010
Effect of blood pressure lowering and intensive glucose control on retinopathy in patients with type 2 diabetes mellitus
In this substudy (AdRem) of ADVANCE, blood pressure lowering or intensive glucose control did not significantly reduce the incidence and progression of retinopathy, although consistent trends towards a benefit were observed, with significant reductions in some lesions observed with both interventions.
Beulens JW, Patel A, Vingerling JR, Cruickshank JK, Hughes AD, Stanton A, Lu J, McG Thom SA, Grobbee DE, Stolk RP; AdRem project team; ADVANCE management committee

In this randomized, controlled 2 x 2 factorial substudy (AdRem) of ADVANCE (a double-blind comparison of blood pressure lowering with a fixed combination of the ACE inhibitor perindopril and the diuretic indapamide vs placebo, and an open comparison of standard vs intensive glucose control targeting a HbA1c level of ≤ 6.5%), baseline and final seven-field stereoscopic retinal photographs assessing diabetic retinopathy were obtained from 1,602 diabetic patients.

Primary outcome

Progression of ≥ 2 steps according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) classification (based on the eye with worst grading).

Main results
  • Retinopathy progressed in 59 (4.8%) patients and developed in 128 (10.3%) patients over 4.1 years.
  • Fewer patients on blood pressure-lowering treatment (n = 623) experienced incidence or progression of retinopathy compared with patients on placebo (n = 618), but the difference was not significant (OR 0.78; 95% CI 0.57-1.06; p = 0.12).
  • Blood pressure-lowering treatment significantly reduced the occurrence of macular edema (OR 0.50; 95% CI 0.29-0.88; p = 0.016) and arteriovenous nicking compared with placebo (OR 0.60; 95% CI 0.38-0.94; p = 0.025).
  • Compared with standard glucose control (n = 611), intensive glucose control (n = 630) did not reduce (p = 0.27) the incidence and progression of retinopathy (OR 0.84; 95% CI 0.61-1.15).
  • Lower, borderline significant risks of microaneurysms, hard exudates, and macular edema were observed with intensive glucose control, adjusted for baseline retinal hemorrhages status.
  • The effects of standard and intensive glucose control were independent and additive.


In the Retinal Measurements study, a substudy (AdRem) of ADVANCE 1 conducted between 2001 and 2008, there was evidence that blood pressure lowering with perindopril-indapamide compared with placebo did not significantly reduce the incidence or progression of retinopathy in diabetic patients, despite a significant reduction in the occurrence of macular edema and arteriovenous nicking over a 4.1 year follow-up period. Vascular changes, namely macular edema and arteriovenous nicking are associated with hypertension and endothelial dysfunction and are predictors of the progression of retinopathy.

Intensive glucose control compared with standard glucose control did not reduce the incidence and progression of retinopathy. However, borderline significant risks of microaneurysms, hard exudates and macular edema were decreased as a result of intensive glucose control. The trends observed were independent of initial blood pressure and HbA1c levels.

While not being significant, the incidence and progression of retinopathy (as assessed by ≥ 2 steps of progression in ETDRS classification) observed after 4.1 years of blood pressure lowering showed a similar risk reduction as the 25% observed in the UKPDS trial after 4.5 years of follow-up, which increased to 34% after 7.5 years of follow-up.2,3 However, unlike the UKPDS study of patients with diabetes and hypertension, the ADVANCE study included patients irrespective of initial blood pressure level. The initial blood pressure values and their mean reductions were therefore much lower than observed in the UKPDS. In addition, in AdRem patients had well-established type 2 diabetes (diagnosed at age 30 years or older and 55 years or older at study entry) and thus differ in this point with the UKPDS population of newly-diagnosed patients.

No risk reduction in laser coagulation therapy was observed, which was in keeping with the entire ADVANCE study.4

Intensive blood glucose-lowering treatment did not significantly affect the incidence and progression of retinopathy, and again the results were consistent with the UKPDS.2 The findings suggest that a longer period of intensive glucose control may be required for a clinically-relevant risk reduction in retinopathy.

In conclusion, the AdRem study did not demonstrate significant reductions of retinopathy either with blood pressure-lowering treatment or with intensive glucose control. There was a huge residual risk of progression of this microvascular complication of diabetes with both treatments, amounting to 78% with blood pressure control and 84% with intensive glucose control.

Figure 1. Mean changes in (a) systolic (SBP) and diastolic blood pressure (DBP) according to blood pressure lowering treatment, and (b) mean HbA1c according to blood glucose-lowering treatment among 1241 type 2 diabetes patients in the AdRem study.
Key to (a) squares – placebo; triangles – perindopril-indapamide; difference in SBP (black squares/triangles): 6.1+1.2 mmHg (p<0.001); difference in DBP (white squares/triangles): 2.3+0.6 mmHg (p<0.001).
Key to (b) squares, standard glucose control; triangles, intensive glucose control; difference in mean HbA1c 0.7+0.1% (p<0.001). R, randomization.
  1. Patel A; ADVANCE Collaborative Group, MacMahon S, Chalmers J, Neal B, 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 Sep 8;370(9590):829-40.
  2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
  3. Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia 2001;44:156-63.
  4. 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;358:2560-72.