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Microvascular Residual Risk Studies

22 August 2016
VADT: Reduced diabetic retinopathy progression on intensive glycaemic therapy with higher HDL cholesterol levels
Higher plasma high-density lipoprotein cholesterol (HDL-C) concentration was consistently associated with improved response to intensive glycaemic therapy in 5-year follow-up of the Veterans Affairs Diabetes Trial (VADT).
Azad N, Bahn GD, Emanuele NV et al. Association of blood glucose control and lipids with diabetic retinopathy in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care 2016;39:816-22.
Objective: To investigate whether lipids modify the relationship between intensive glucose control and diabetic retinopathy (DR)
Study design: Post hoc analysis of the VADT, an open-label prospective, randomized controlled trial targeting patients with poorly controlled type 2 diabetes, randomized to intensive or standard glycaemic control.
Study population: 858 of 1,791 patients enrolled in VADT who had 7-field stereoscopic fundus photographs at baseline and 5 years later. Each eye was individually graded, and the eye with worse DR was used for the analysis.
Efficacy measures:

·       Onset of DR, defined by the development of eye outcomes during the study in individuals with a previous report of absence of microaneurysms and other characteristics of DR using the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale (level 10) at the beginning of the study.

·       Progression of DR, defined as changes in ETDRS severity scale of two steps or more between the baseline and 5-year follow-up.

Methods: Multiple logistic regression analysis including the following variables: age, HbA1c, duration of diabetes, cardiovascular disorders, body mass index, systolic and diastolic blood pressure, estimated glomerular filtration rate, fibrinogen, plasminogen activator inhibitor 1, C-peptide, and history of eye disorders. The impact of various lipids at baseline, the end of the study, and changes during the study and their interaction with intensive glycaemic control on progression of DR was investigated.  The longitudinal mixed effects model was used to assess the lipids repeated measures for 5 years between the two treatment arms.  
Main results:

Overall, 595 patients had DR at baseline (305 on intensive glycaemic control and 290 on standard control). Of these, 120 (20%) experienced progression of DR during the study. The likelihood of DR progression was reduced by ∼40% in patients with total cholesterol ≤140 mg/dL, triglycerides ≤ 120 mg/dL or HDL-C ≥45 mg/dL at 5 years (Table 1).

Table 2. DR progression at 5 years (intensive vs standard treatment)

Parameter at end of study

Odds ratio


Total cholesterol ≤140 mg/dL

0.62 (0.39–0.97)


LDL cholesterol ≥120 mg/dL


NS, p=0.07

HDL cholesterol ≥45 mg/dL

0.62 (0.40–0.99)


Triglycerides ≤120 mg/dL

0.63 (0.4–0.98)


Notably, reduction in LDL cholesterol by ≥40 mg/dL reduced the odds of DR progression by 44% (odds ratio 0.56; 95% CI 0.35–0.89; p= 0.004), and reduction in triglycerides by ≥60 mg/dL reduced the odds of DR progression by 38% (odds ratio 0.62; 95% CI 0.40–0.98, p=0.004).
Authors’ conclusion: Intensive glycaemic control was associated with decreased odds of progression but not with onset of retinopathy in patients with worse lipid levels at baseline and more improved lipid levels during the study. Higher HDL-C was consistently associated with better response to intensive glycaemic control throughout the study


As shown previously and in this analysis, the Veterans Affairs Diabetes Trial showed no significant association between glycaemic treatment assignment or improved lipid management on the risk for DR onset and/or progression (1). However, this report highlights an interaction between glycaemic and lipid control, as patients in the intensive glycaemic arm with improved management of total and LDL cholesterol, triglycerides and HDL-C during the study benefited most in terms of reduction in risk of DR progression. These findings are consistent with a recent report from an observational study including 72,267 individuals with type 2 diabetes, in which the risk of microvascular events (retinopathy, nephropathy, and neuropathy) was reduced with improved lipid control, irrespective of whether lipid goals were attained (2).

 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed reduction in the risk of DR progression with intensive glycaemic control or lipid control fenofibrate in type 2 diabetes patients (3). Further analysis suggested that these effects may be additive, as the incidence of progression of ≥3-steps of the ETDRS or photocoagulation was nearly three-fold lower among patients assigned to both intensive glycaemic control and fenofibrate, compared with patients assigned to neither (4.8% versus 13.1%) (4).

 Taken together, these data lend support to the need for multifactorial intervention, targeting not only glycaemia and LDL cholesterol, but also atherogenic dyslipidaemia (elevated triglycerides and low HDL-C) in type 2 diabetes patients to reduce the risk of progression of diabetes-related microvascular complications. However, the available data do not offer insights into the mechanisms of this interaction between intensive glycaemic and lipid control, which, given the complex pathophysiology underlying the development of DR (5), is perhaps not surprising. Indeed, there is emerging evidence that the benefit of management of atherogenic dyslipidaemia with fenofibrate may relate to non-lipid factors, including an effect on reduction in excess vascular permeability (6).


1. Duckworth W, Abraira C, Moritz T et al. VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–39.

2. Toth PP, Simko RJ, Palli SR et al. The impact of serum lipids on risk for microangiopathy in patients with type 2 diabetes mellitus. Cardiovascular xx2012;11:109–18.

3. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-44.

4. Chew EY, Davis MD, Danis RP et al. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology 2014;121:2443-51.

5. Tarr JM, Kaul K, Chopra M, Kohner EM, Chibber R. Pathophysiology of diabetic retinopathy. ISRN Ophthalmol 2013;2013:343560.

6. Roy S, Kim D, Hernández C, Simó R2, Roy S. Beneficial effects of fenofibric acid on overexpression of extracellular matrix components, COX-2, and impairment of endothelial permeability associated with diabetic retinopathy. Exp Eye Res 2015;140:124-9.

Key words diabetic retinopathy; type 2 diabetes; glycaemic control; lipid control; atherogenic dyslipidaemia