Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy.

Morton J, Zoungas S, Li Q, et al; on behalf of the ADVANCE Collaborative Group. Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy. Diabetes Care. 2012;35:2201-2206. 

Exclusive! Vivian Fonseca, MD, provides expert commentary on this post-hoc analysis of ADVANCE.
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Macro- and microvascular complications remain significant concerns in the treatment of patients with type 2 diabetes. Controlling for factors such as A1C and blood pressure can help to address these concerns; however, identification of additional risk factors could be beneficial in personalizing treatment strategies for patients, taking into account their individual risk profiles.

Low levels of high-density lipoprotein cholesterol (HDL-C) are a risk factor that was shown to be significantly associated with macrovascular complications (specifically, coronary artery disease) in the United Kingdom Prospective Diabetes Study (UKPDS).1 Could low HDL-C have an effect on microvascular complications, as well?

ADVANCE Post-hoc Analysis Design  

The authors of the current analysis investigated the hypothesis that lower HDL-C levels may predispose patients to the development and progression of microvascular complications; it is the largest prospective analysis that specifically addresses the relationship between HDL-C and microvascular disease risk among those with type 2 diabetes.

Subjects included in this post-hoc analysis were members of The Action in Diabetes and Vascular Disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) cohort with HDL-C measurements at baseline (N=11,126). ADVANCE examined the effects of standard vs intensive glucose-control interventions on major macro- and microvascular events among subjects who were aged ≥55 years and had type 2 diabetes and ≥1 other cardiovascular risk factor. Findings from ADVANCE published in 2008 showed that patients treated with intensive glucose control had greater reduction in the rates of combined major macro- and microvascular events (18.1% intensive therapy vs 20.0% standard therapy; hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.82-0.98; P=0.01) and microvascular events alone (9.4% intensive therapy vs 10.9% standard therapy; HR, 0.86; 95% CI, 0.77-0.97; P=0.01) over median follow-up of 5 years, although the between-group differences were small.2 The decreased rate of microvascular events was primarily due to a 21% decrease in nephropathy (4.1% in the intensive-therapy group vs 5.2% in the standard-therapy group; HR, 0.79; 95% CI, 0.66–0.93; P=0.006), as no significant effect on retinopathy was observed in either treatment group (P=0.50).2  

The main outcome assessed in the current analysis was microvascular events, defined as a composite of total renal and retinal events.* (Click here for slide.)  


Over a median follow-up of 5 years, 32% (n=3,585) of subjects developed a new or worsening microvascular event.

  • 28% (n=3,161) had a renal event
  • 6% (n=680) had a retinal event

Event risk was compared based on three tertiles of baseline HDL-C: tertile 1: <42.5 mg/dL, tertile 2: 42.5-51.8 mg/dL, and tertile 3: >51.8 mg/dL. A 17% higher risk for microvascular events was seen among subjects in the lowest vs the highest HDL-C tertile (See Table.).  

Lower baseline levels of HDL-C significantly and independently predicted the development and progression of nephropathy. Subjects in the lowest tertile of baseline HDL-C had a 19% higher nephropathy risk vs subjects in the highest tertile (See Table.).  

No association was observed between baseline HDL-C and retinopathy risk (See Table.). (Click here for slide.)  


  Lowest vs highest HDL-C tertile; HR (95% CI)   P  
Microvascular events (total) 1.17 (1.06-1.28) 0.001
Nephropathy 1.19 (1.08-1.32) 0.0005
Retinopathy 1.01 (0.82-1.25)



At baseline, evidence of microvascular disease was present among 10% of subjects (n=1,155), and mean HDL-C was 50.3 mg/dL.

*Total renal events: development of new microalbuminuria, new macroalbuminuria, doubling of creatinine to ≥200 µmol/L, need for renal replacement therapy, or death due to renal disease; total retinal events: development of proliferative retinopathy, macular edema, blindness related to diabetes, use of retinal photocoagulation therapy

Adjusted for regression dilution and potential confounders

1. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS). BMJ. 1998;316(7134):823-828.

2. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New Engl J Med. 2008;358(24):2560-2572.

Related content: 

Clinical Insights® in Diabetes :: December 2012  

Slide: ADVANCE: Study Design  

Slide: ADVANCE: Death from Any Cause  

Slide: ADVANCE: Primary Endpoints  

Slide: ADVANCE Trial: Intensive Blood Glucose Control in Patients With Type 2 Diabetes  

Slide: ADVANCE Trial: Combined Major Macrovascular and Microvascular Events  

Slide: ADVANCE Trial: Risk for Major Macrovascular and Microvascular Events  

Expert commentary: Burton E. Sobel, MD, provides expert commentary on the debate over intensive versus somewhat less intensive glycemic control (You must be a registered member of NDEI.org to view.)  


December 2012

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.

Last Modified: 8/5/2014