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13 February 2014
REALIST-Micro: Diabetic microvascular complications associated with atherogenic dyslipidaemia

REALIST-Micro showed a robust association between higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol (HDL-C) and diabetic kidney disease in patients with type 2 diabetes and controlled low-density lipoprotein cholesterol (LDL-C) levels.

Sacks FM, Hermans MP, Fioretto P, Valensi P, Davis T, Horton E, Wanner C, Al-Rubeaan K, Aronson et al. .Association between plasma triglycerides and HDL-cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes: A global case-control study in 13 countries. Circulation 2013 Dec 18. [Epub ahead of print].
Summary
Comments & References
STUDY SUMMARY
Objective To investigate the relation between plasma lipids, specifically triglycerides and HDL C, and microvascular disease in patients with type 2 diabetes and well-controlled plasma LDL-C levels.
Study design Cross-sectional case-control study in 24 sites in 13 countries.
Study population

Individuals aged ≥40 years with type 2 diabetes (as documented in medical records), and plasma LDL-C levels ≤3.4mmol/L (132 mg/dL). Cases (n=2,535) were patients with visits for at least one documented ocular or renal microvascular complication; controls (n=3,683) had no documented evidence of microvascular complications of the kidney and eye (see below in Methods), and were matched within sites and within strata defined by gender.

Primary variable • Diagnosis of kidney disease and/or retinopathy as defined in Methods
• Total cholesterol, HDL-C, LDL-C (measured directly or calculated) and triglycerides (73% of cases and 76% of controls were fasting levels)
Methods Kidney disease was defined as either proteinuria >300 mg/L, albuminuria (albumin/creatinine ratio ≥30 μg/mg measured in a single morning urine sample; or>20 μg/min in timed overnight urine collections; or >30 mg/24h in a 24-hour urine), or estimated glomerular filtration rate <60 ml/min/1.73m2, according to the Modification of Diet in Renal Disease formula. Retinopathy (including diabetic macular oedema) was defined as laser treatment for diabetic retinopathy; Early Treatment Diabetic Retinopathy (ETDRS) staging ≥20 on fundus photography; Diabetic Retinopathy Disease Severity Scale 3, 4 or 5 on dilated ophthalmoscopy, or moderate or severe maculopathy (Diabetic Macular Edema Disease Severity Scale).
The index visit for a case was a complication-related visit to which a lipid panel measured within 6 months could be assigned. Matched analysis was performed using site-specific conditional logistic regression in multivariable models that adjusted for haemoglobin A1c, hypertension, and statin treatment.
Main results

Among cases, 1,891 had kidney disease, 1218 had retinopathy and 574 cases had both kidney and eye disease (Table 1). Overall, mean LDL-C was 2.3 mmol/L (89 mg/dL).

Table 1. Patient characteristics

 

All cases (N=2535)

Kidney cases (N=1891)

Eye cases (N=1202)

Controls (N=3683)

Male

58%

61%

54%

55%

White

44%

44%

41%

51%

Mean age, yr

65±11

65±11

64±10

62±11

Mean duration of diabetes, yr

14±9

14±9

16±9

10±8

Mean HbA1c

8.1%

8.0%

8.3%

7.6%

Lipids, mmol/L*

 

 

 

 

Total cholesterol

4.30±0.92

4.26±0.84

4.36±1.02

4.30±0.83

LDL-C

2.31±0.63

2.28±0.64

2.34±0.62

2.35±0.85

HDL-C

1.20±0.44

1.18±0.46

1.23±0.40

1.26±0.45

Triglycerides

1.78±1.14

1.85±1.17

1.72±1.18

1.61±1.20

Lipid-lowering therapy

 

 

 

 

  Statin

52%

56%

48%

51%

  Fibrate

7.7%

8.6%

6.7%

7.9%

Data are given as mean ±SD or mean except where indicated; * To convert triglycerides to mg/dL multiple by 88.5; to convert other lipids to mg/dL multiply by 38.7.

Triglycerides and HDL-C were significantly and independently associated with diabetic microvascular complications, specifically diabetic kidney disease. This association was less robust for diabetic retinopathy (Table 2). Patients with triglycerides in the highest quintile (³2.83 mmol/L or ³250 mg/dL) had a 76% increase in risk for microvascular complications compared with those with lowest levels £0.74 mmol/L (~65 mg/dL). In addition, patients with HDL-C in the highest quintile (³1.7 mmol/L or 66 mg/dL) had a 27% decrease in risk for microangiopathy compared with those with HDL-C levels £0.82mmol/L (32 mg/dL).
Most notably, the risk of diabetic kidney disease was increased more than 2.2-fold for patients with triglycerides in the highest quintile versus those in the lowest (Hazard ratio 2.24, 95% CI 1.78-2.83).

Table 2. Triglycerides, HDL-C and risk for microvascular complications

 

Change in risk
Hazard ratio (95% CI)

Any microvascular complication

 

Each ­ by 0.5 mmol/L in TG

1.16 (1.11-1.22)

Each ­ 0.2 mmol/L in HDL-C

0.92 (0.88-0.96)

 

Diabetic kidney disease

 

Each ­ by 0.5 mmol/L in TG

1.23 (1.16-1.31)

Each ­ 0.2 mmol/L in HDL-C

0.86 (0.82-0.91)

 

 

Retinopathy

 

Each ­ by 0.5 mmol/L in TG

1.09 (1.02-1.16)*

Each ­ 0.2 mmol/L in HDL-C

0.93 (0.86-1.0)*

* Matched analysis including hypertension and haemoglobin A1c weakened these associations

Author's conclusion Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of HDL-C among patients with good control of LDL C. Retinopathy was less robustly associated with these non-LDL lipids. These results strengthen the rationale for studying dyslipidaemia treatment to prevent diabetic microvascular disease.
 

COMMENT

Patients with type 2 diabetes treated with optimal standards of care for control of blood glucose, blood pressure and LDL-C remain exposed to a high residual risk for microvascular complications.(1,2)  This issue has been previously highlighted by the Residual Risk Reduction Initiative.(3) Whether tighter control of blood glucose and/or blood pressure might reduce this level of risk is contentious. With respect to intensification of blood pressure lowering, the ADVANCE trial indicated a beneficial effect on the risk for renal events, mainly albuminuria, in diabetes patients, but no improvement in diabetic retinopathy.(4,5) Furthermore, while blood pressure lowering with olmesartan reduced the incidence of microalbuminuria in the ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) trial, there was also a real-world excess in cardiovascular mortality, as well as decline in the estimated glomerular filtration rate.(6) With respect to intensification of glycaemic control, ACCORD-Eye showed significant improvement in the risk of progression of diabetic retinopathy with intensive glycaemic control, although this needs to be weighed against the lack of cardiovascular benefit and excess mortality observed in the overall ACCORD study.(7,8)

A growing body of evidence links non-LDL lipids, specifically triglycerides and HDL-C, with risk for diabetic microvascular complications.(9) Key findings of the REALIST-Micro study reinforce this. In particular, REALIST-Micro demonstrates a significant and robust worldwide association between plasma triglycerides or HDL-C and diabetic renal disease, even after adjustment for hypertension and HbA1c. The associations between triglycerides, HDL-C and diabetic retinopathy were less robust, which is not surprising given that multiple pathways are implicated in the underlying pathophysiology of this diabetic complication.(10)

Recent guidelines for management of dyslipidaemia suggest that a triglyceride level of <1.7 mmol/L (150 mg/dL) is desirable.(11) However, REALIST-micro showed that even among patients with triglycerides between 1.36 and <1.77 mmol/L (~120 and 160 mg/dL), there is about 1.5-fold increase in risk for diabetic renal disease. Among patients with markedly elevated triglycerides (³2.83 mmol/L or ~250 mg/dL), there was a >2-fold increase in risk, based on mutually adjusted data.

While the authors acknowledge the limitations inherent with a cross-sectional design, heterogeneity with respect to lipid measurement across the centres and the potential for reverse causation, there are also important strengths of this study. REALIST-Micro was a global study involving a large number of cases across 13 countries in Europe, North America, the Middle East, Asia (including Japan and China), and Australasia. Sensitivity analyses showed similar results in these geographic regions. Consequently, the findings of REALIST-Micro have important clinical implications. Targeting atherogenic dyslipidaemia, i.e. elevated plasma triglycerides and low-HDL-C, which are common in patients with type 2 diabetes, offers the potential for significant reduction in the residual risk of diabetic renal disease. Indeed, it is noteworthy that studies with fibrates (i.e. gemfibrozil, bezafibrate and fenofibrate), which reduce plasma triglycerides by up to 40%, depending on baseline levels, have shown preventive effects on the progression of albuminuria(.12-16) Overall, the results of REALIST-Micro support a multifaceted approach, including targeting of atherogenic dyslipidaemia, to reduce the residual risk of diabetic renal disease in type 2 diabetes patients.  

References

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2. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580-91.
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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: 2560-2572.
5. ADVANCE Collaborative Group, Patel A, 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: 829-840.
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16. Nagai T, Tomizawa T, Nakajima K, Mori M. Effect of bezafibrate or pravastatin on serum lipid levels and albuminuria in NIDDM patients. J Atheroscler Thromb 2000;7: 91-96.