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10 October 2012
New data from ADVANCE: Low HDL cholesterol is an independent predictor of diabetic nephropathy in type 2 diabete

An analysis of data from over 11,000 type 2 diabetes patients showed that the presence of low plasma high-density lipoprotein cholesterol (HDL-C) was significantly predictive of the risk for development and progression of diabetic nephropathy. These patients had a 19% increase in risk of renal events, compared with those with higher HDL-C levels. Targeting low HDL-C, a component of atherogenic dyslipidemia, or the abnormalities underlying its decrease, may therefore be of value in reducing the residual risk of renal events in type 2 diabetes.

Morton J, Zoungas S, Li Q et al.
Comments & References
To test whether low HDL-C is associated with increased risk for microvascular events in type 2 diabetes patients
Study polupation 11,140 patients with type 2 diabetes and at least one additional vascular risk factor, included in the ADVANCE (Action in Diabetes and Vascular Disease: preterAx and diamicroN-MR Controlled Evaluation) study.
Key outcomes

       Primary outcome:

  • Microvascular events, defined as a composite of total renal and retinal events. Only the first event was analysed.

       Secondary outcomes:

  • Total renal events: development of new onset microalbuminuria (urinary albumin:creatinine ratio [ACR] 30-300 mg/mg); new onset macroalbuminuria (ACR >300 mg/mg); doubling of creatinine to at least 200 mmol/L; need for renal replacement therapy; or death due to renal disease
  • Total retinal events: development of proliferative retinopathy; macular oedema; diabetes-related blindness; use of retinal photocoagulation therapy
Main results
  • At baseline (study entry) 10% (n=1,155) of patients had microvascular disease
  • During a median 5 year follow-up period:
    • 32% (n=3,585) of patients developed new or worsening of microvascular disease
    • 28% of all patients (n=3,161) developed a renal event, most commonly microalbuminuria, and 6% (n=680) developed a retinal event, most commonly the need for laser therapy
  • At baseline, mean (SD) HDL-C was 1.3 (0.45) mmol/L
    • Low HDL-C at baseline (<1.1 mmol/L or 43 mg/dL) was associated with higher triglycerides and lower total and low-density lipoprotein cholesterol (LDL-C). Mean triglycerides were 2.3 mmol/L (204 mg/dL)  in patients in the lowest HDL-C tertile versus 1.7 mmol/L (150 mg/dL) in patients in the highest HDL-C tertile (p<0.0001).
  • After adjustment for regression dilution and demographic and vascular risk factors*, patients in the lowest HDL-C tertile had a 17% increase (95% CI 6-28%) in risk for microvascular events compared with those in the highest HDL-C tertile (p=0.001).
  • This increased microvascular risk was largely driven by a 19% (95% CI 8-32%) higher risk for renal events (p=0.0005).
  • Patients with HDL-C in the lowest tertile were at significantly higher risk of developing new-onset microalbuminuria (by 14%, 95% CI 3-27%, p=0.01), or new-onset macroalbuminuria (by 42%, 95% CI 7-87%).
  • In contrast, there was no association between baseline HDL-C and retinal outcomes (hazard ratio 1.01, 95% CI 0.82-1.25, p=0.90

* These included baseline age, sex, ethnicity, history of microvascular disease, smoking, alcohol intake, HbA1c, body mass index, systolic blood pressure, diabetes duration, statin use and baseline creatinine, total cholesterol and triglycerides.



In this analysis from the ADVANCE study, low HDL-C was a significant, independent prognostic factor for the development of renal events, in particular new-onset albuminuria in patients with type 2 diabetes. The increase in risk associated with low HDL-C (19%) was generally similar with that previously reported in smaller studies.(1) While the study findings are strengthened by the large cohort size, it should be borne in mind that this was a post hoc observational analysis and therefore subject to the limitations inherent in this type of analysis.

The lack of association between HDL-C and retinal events is not unexpected. Both the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and ACCORD (Action to Control Cardiovascular Risk in Diabetes)-Eye studies did not show an association between changes in lipid levels (including HDL-C) and progression of diabetic retinopathy.(2,3) Indeed, given the involvement of multiple pathways in the pathogenesis of diabetic retinopathy,4 it is unlikely that specifically targeting one component of routine lipids would produce significant clinical benefit.

Finally, given the metabolic interrelationships between HDL and triglycerides, it would be of interest to investigate the association of atherogenic dyslipidemia, the combination of low HDL-C and elevated triglycerides, with residual risk of diabetic nephropathy.


1. Zoppini G, Targher G, Chonchol M et al. Higher HDL cholesterol levels are associated with lower incidence of chronic kidney disease in patients with type 2 diabetes. Nutr Mteab Cardiovasc Dis 2009;19:580-6.
2. Keech AC, Mitchell P, Summanen PA, et al; FIELD study investigators.  Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97.
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. Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med 2012;366:1227-39.