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26 October 2009
Elevated triglycerides levels accelerate progression of diabetic neuropathy in type 1 and type 2 diabetes

Among patients with diabetic neuropathy followed up to one year, those with hypertriglyceridemia had markedly higher loss of sural myelinated fibers compared to those with normal triglycerides levels.

Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AAF, Feldman EL
Summary
Comments & References
STUDY SUMMARY
Methods

Using sural nerve biopsies to assess changes in sural nerve myelinated fiber density (MFD) over a 52-week period in 427 type 1 and type 2 diabetic patients with neuropathy, Wiggin et al. defined 2 groups of patients with:

  • progressing diabetic neuropathy (loss of ≥500 fibers/mm2 in sural nerve MFD over 52 weeks);
  • non-progressing diabetic neuropathy (MFD loss of ≤100 fibers/mm2 over the same period).

To identify predictors of diabetic neuropathy, baseline participant’s characteristics were compared between the two groups (clinical signs and symptoms, electrophysiological measurements, HbA1c, triglycerides, cholesterol, albumin, and hematocrit). Two analyzes were conducted:

  • in the primary analysis, variables were tested for a simple correlation with the rate of MFD loss;
  • in the secondary analysis, correlations were measured in groups balanced on the basis of initial diabetic neuropathy status, including initial MFD, diabetes type (1 or 2), and insulin treatment.

These analyses were performed on samples and data from participants in two identical, randomized placebo-controlled clinical diabetic neuropathy trials testing acetyl-L-carnitine (ALC).1 Eligibility criteria included HbA1c >5.9%, age between 18 and 70 years, diabetes duration of >1 year, and diabetic neuropathy as defined by the San Antonio Conference.2 Because ALC treatment did not affect sural nerve MFD loss in these trials (p=0.87), data from patients receiving the active treatment were pooled with those of patients on placebo.

Main results

In the primary analysis, five baseline variables were significantly correlated with loss of sural nerve MFD over 52 weeks: dominant peroneal motor nerve conduction velocities (NCV; p = 0.005), non-dominant median motor NCV (p = 0.02), sural sensory NCV (p = 0.05), HbA1C (p = 0.02), and triglycerides level (p = 0.02).

In the secondary analysis, baseline triglycerides were significantly higher (p=0.04) and peroneal motor NCV significantly lower (p=0.008) in the progressing group. No correlations were found with the other variables.

COMMENT

A comprehensive knowledge of the causes and mechanisms of diabetic neuropathy is still lacking. Major studies such as the Diabetes Control and Complications Trial (DCCT) have reported a positive correlation with the most commonly-used non-invasive biomarker of chronic hyperglycemia, namely HbA1c.3 There is also a growing body of evidence attracting attention on a possible etiological role of dyslipidemia in diabetic microangiopathies. For example, in the EURODIAB study, cholesterol and fasting triglycerides were significantly associated with the development of diabetic neuropathy.4 In the FIELD study, lipid-modifying therapy with fenofibrate reduced the incidence of macrovascular events and microvascular complications of type 2 diabetes, the latter including retinopathy, nephropathy, and autonomic neuropathy.5
The study by Wiggin et al. was designed to evaluate the mechanisms underlying diabetic neuropathy progression in a study population with both type 1 and type 2 diabetes. The primary outcome measure they used, MFD, is a quantitative and highly-reproducible measure of nerve health. The most relevant results of the study are those of the secondary analysis, in which the two groups of progressors and non-progressors were well-balanced in terms of initial diabetic neuropathy status, diabetes type, and use of insulin therapy – all factors known to have a significant impact on neuropathy development and/or progression.
This analysis identified high fasting triglycerides levels as the only independent variable associated with progression of diabetic neuropathy. The other correlate, peroneal motor nerve conduction velocities, is obviously linked to the neuropathy itself.
As stressed by the authors, these findings support the emerging idea that atherogenic dyslipidemia contributes to the development of diabetic neuropathy. This, they continue, may explain the earlier incidence of diabetic neuropathy in individuals with type 2 compared with type 1 diabetes, since the latter often have normal to supranormal triglycerides levels, as a combined result of (i) lack of endogenous portal insulin secretion, (ii) decreased incidence of metabolic syndrome and obesity, (iii) normal mean insulin sensitivity, and (iv) systemic hyperinsulinemia. Dyslipidemia develops thus later (if at all) in the course of type 1 diabetes despite lesser use of lipid-lowering therapies, and the delayed development of an abnormal lipid profile coincides with the delayed onset and progression of diabetic neuropathy.6,7

The identification of hypertriglyceridemia as the main risk factor for diabetic neuropathy progression besides hyperglycemia suggests that lipid-modifying therapy might potentially impact on residual risk of diabetic neuropathy that is not eliminated by adequate glycemic control. Results of the FIELD study showing a significant decrease in non-traumatic amputations, the most dramatic consequence of peripheral diabetic neuropathy and vascular microangiopathy, in patients treated with fenofibrate, are particularly encouraging in this respect.8

h

Figure 2. Fasting triglycerides levels in patients with non-progressing
and progressing diabetic neuropathy followed up to 52 weeks. *p=0.

References
  1. Sima AA, Calvani M, Mehra M, Amato A. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care 2005;28:89–94.
  2. American Diabetes Association. Clinical practice recommendations 1995.Diabetes Care 1995;18 (Suppl. 1):1–96.
  3. Chisholm DJ. The Diabetes Control and Complications Trial (DCCT): a milestone in diabetes management. Med J Aust 1993;159:721–3.
  4. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341–50.
  5. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M; FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005 Nov 26;366(9500):1849-61.
  6. Tomlin AM, Dovey SM, Tilyard MW. Risk factors for hospitalization due to diabetes complications. Diabetes Res Clin Pract 2008;80:244–252
  7. Chaturvedi N, Sjoelie AK, Porta M, Aldington SJ, Fuller JH, Songini M, Kohner EM. Markers of insulin resistance are strong risk factors for retinopathy incidence in type 1 diabetes. Diabetes Care 2001;24:284–9.
  8. Rajamani K, Colman PG, Li LP, Best JD, Voysey M, D'Emden MC, Laakso M, Baker JR, Keech AC; FIELD study investigators. 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.