Reducing residual microvascular risk in diabetes: an unmet clinical priority. A review of the evidence implicating atherogenic dyslipidemia

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1 January 2010

This review, written by members of the R3i International Steering Committee, evaluates the role of atherogenic dyslipidemia in diabetic microvascular residual risk. Summary of evidence and clinical implications.

Fioretto P, Dodson PM, Ziegler D, Rosenson RS

STUDY SUMMARY

Review aim

This review highlights the urgent - and so far unmet - need to address the high residual microvascular risk in patients with diabetes managed according to current standards of care.

The aims were to evaluate:

the role of atherogenic dyslipidemia in residual microvascular risk, and
whether lipid-modifying therapy targeting elevated TG and/or low HDL-C reduced this risk.

Review criteria

Medline was searched over the period 1960-2008 using the search terms: ‘diabetes’, ‘microvascular disease’, ‘diabetic retinopathy’, ‘diabetic nephropathy’, ‘diabetic neuropathy’, ‘coronary microvascular’, ‘lipids’, ‘treatment’, ‘prevention’ and ‘trial’, and MeSH equivalents.

Main findings

Diabetic retinopathy
Findings suggested an association between elevated TG and/or low HDL-C and progression of diabetic retinopathy.

In the DCCT/EDIC trial (type 1 diabetes), nuclear magnetic resonance analysis showed that the severity of retinopathy in males was:

Positively associated with elevated levels of TG, LDL-C, small LDL particles and apolipoprotein B.
Negatively associated with HDL-C level

Of the available lipid-modifying interventions, the extent of evidence was greatest for fibrates, especially fenofibrate.

Previous studies with clofibrate suggested beneficial effects in diabetic maculopathy.
In the FIELD study (type 2 diabetes), 5-year treatment with fenofibrate:

Reduced requirement for inaugural laser treatment for retinopathy by 31% (from 4.9% to 3.4%, P=0.0002).
Reduced progression of retinopathy (by 2 steps on the ETDRS grade, from 14.6% to 3.1%, P=0.004) in patients with pre-existing disease in the ophthalmology substudy group.
However, baseline lipids appeared to be similar in patients who did and did not undergo laser treatment.

Diabetic nephropathy
In the UKPDS (newly-diagnosed type 2 diabetes), elevated TG and low HDL-C at baseline were associated with increased risk for progression of diabetic nephropathy.

Lipid parameter	Nephropathy marker	Hazard ratio [HR] (95% CI)	P value
Elevated TG	Microalbuminuria	1.09 (1.04 to 1.14)	<0.0001
	Macroalbuminuria	1.15 (1.09 to 1.21)	<0.0001
Low HDL-C	Doubling of serum creatinine	2.78 (1.01 to 7.68)	<0.05

Both the DAIS and FIELD trials showed that fenofibrate treatment significantly attenuated progression of albuminuria in type 2 diabetic patients managed according to current standards of care. In FIELD, fenofibrate treatment was associated with 14% less progression and 15% more regression of albuminuria (P=0.002).

Diabetic neuropathy
The EURODIAB trial (type 1 diabetes) identified elevated TG, total-C and LDL-C, and low HDL-C as risk factors for diabetic neuropathy.

The Fremantle Diabetes Study (type 2 diabetes) also showed that lipid-modifying treatment was associated with significant reduction in incident neuropathy, suggestive of protective effects:

For statin: HR 0.65, 95% CI 0.46 to 0.93, P<0.05.
For fibrate: HR 0.52, 95% CI 0.27 to 0.98, P<0.05.

In the FIELD study, fenofibrate treatment for 5 years markedly reduced the occurrence of a first non-traumatic amputation event by 36% (P=0.02), especially minor (i.e. more distal) amputation in patients without known large vessel disease (relative risk reduction, 47%, P=0.027).

Conclusion

Interventions that target atherogenic dyslipidemia might reduce diabetic microvascular residual risk.

Acronyms
DCCT/EDIC: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications
FIELD: Fenofibrate Intervention and Event Lowering in Diabetes
UKPDS: United Kingdom Prospective Diabetes Study
DAIS: Diabetes Atherosclerosis Intervention Study
EURODIAB: European Diabetes

COMMENT

Burden of residual microvascular risk
Microvascular complications of diabetes, such as retinopathy, nephropathy and non-traumatic lower limb amputation, confer a substantial burden on individuals and their carers, and on healthcare systems. With the ongoing diabetes pandemic, this burden is poised to escalate. While there is no doubt that multifactorial intervention aimed at optimal management of known modifiable risk factors for microvascular disease, such as blood pressure and blood glucose is essential to reduce the risk of microvascular complications, a high residual microvascular risk remains after such an intervention corresponding to current standards of care, which also include management of LDL-C and lifestyle optimization. In the STENO‑2 trial involving 160 type 2 diabetic patients treated for ~8 years, development or progression of diabetic retinopathy was observed in 48%, progression of peripheral neuropathy in 50%, while 20% developed diabetic nephropathy.1 Despite the relatively small sample size, the STENO-2 data clearly highlight the magnitude of residual microvascular risk, even in an ideal trial setting simultaneously targeting multiple risk factors.

Whether further intensification of blood pressure and glycemic control can substantially impact this residual risk is debatable. While ADVANCE showed that intensification of blood pressure control might provide some additional benefit in reducing the risk of diabetic nephropathy,2 a role for improved glycemic control aiming at near-normoglycemia is more contentious. Consequently, attention has focused on other factors, including non-LDL lipid parameters.

Role of atherogenic dyslipidemia
This review is timely as it aims to address the role of atherogenic dyslipidemia in residual microvascular risk in patients with diabetes. The reviewed evidence linking atherogenic dyslipidemia and microvascular complications relates to patients with both type 1 and type 2 diabetes.

Based on their review, the authors conclude that the available evidence from published studies suggests that atherogenic dyslipidemia confers residual microvascular risk in patients with diabetes. Subsequent to this review, evaluation of mechanisms underlying diabetic nerve damage showed that in patients with mild to moderate diabetic neuropathy, elevated TG correlated with loss of sural nerve myelinated fiber density (an index of neuropathy progression), independent of disease duration, age or diabetes control.3

Preliminary findings from the R3i-funded REALIST (REsiduAl risk, LIpids, and Standard Therapies) Microvascular Survey also provide support for a role for atherogenic dyslipidemia in residual microvascular risk. Patients with at least one microvascular complication (diabetic retinopathy, maculopathy or nephropathy) were compared in a case-control design with control type 2 diabetic patients without microvascular complications. Low HDL-C and/or elevated TG were significantly more prevalent in type 2 diabetic patients who subsequently developed microvascular complications. The analysis suggested that elevated TG were associated with incident diabetic retinopathy and nephropathy, and low HDL-C was associated with incident diabetic nephropathy.4

Reducing microvascular residual risk: implications
Whether a strategy targeting atherogenic dyslipidemia, in addition to current standards of care, impacts on residual microvascular risk is as yet an unanswered question.

The authors acknowledge that there are limited data suggesting protective effects of most lipid-modifying interventions. The evidence base is strongest for fenofibrate, with the FIELD and DAIS studies showing significant reductions in progression of albuminuria,5,6 and the FIELD study showing significant reductions in laser treatment for retinopathy,7 and non-traumatic lower-limb amputation.8 These data suggest that adding fenofibrate might reduce microvascular residual risk in type 2 diabetic patients managed according to current standards of care, including LDL-C management using a statin as preferred LDL-C-lowering therapy.

This strategy has been investigated in the ACCORD study comparing the effects of a simvastatin-fenofibrate combination therapy to simvastatin monotherapy. Results of the ACCORD study regarding microvascular endpoints are expected to be released in 2010.

References

1. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93.
2. Patel A, ADVANCE Collaborative Group, 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;370:829-40.
3. Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AA, Feldman EL. Elevated triglycerides correlate with progression of diabetic neuropathy. Diabetes 2009;58:1634-40.
4. REALIST available on this website as a video
5. Keech A, Simes RJ, Barter P, FIELD Study Investigators, et al. Effect of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.
6. Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G; DAIS Investigators. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 2005;45:485-93.
7. Keech AC, Mitchell P, Summanen PA, FIELD Study Investigators, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97. 8. Rajamani K, Colman PG, Li LP, FIELD Study Investigators, et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009;373:1780-8.