21st August 2021, Dr Chee L Khoo
Nothing scares patients with diabetes more than blindness. Although we have many treatment options available for proliferative diabetic retinopathy and macular oedema, diabetes remains the leading cause of severe visual impairment in working-aged adults. Diabetic retinopathy affects one in three people with diabetes. Risk factor control and screening are the cornerstones for retinopathy prevention. Once retinopathy has established though, apart from tight glucose, lipid and blood pressure control, fenofibrate is recommended to slow down the progression of retinopathy. Fenofibrate is used to reduce triglycerides but how does it help to slow down retinopathy progression?
The pathogenesis of diabetic retinopathy is directly related to hyperglycaemia, present in both T1D and T2D. It generally occurs in patients whose HbA1c is >7.0% and we don’t see them in patients with good glycaemic control. But lipid dysmetabolism must a play a part in the pathogenesis.
Fenofibrate is a peroxisome-proliferating receptor α (PPAR-α) commonly used to reduce triglycerides. It was shown to reduce the progression of retinopathy in patients with pre-existing retinopathy in two large placebo-controlled randomised trial.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50–75 years with type 2 diabetes mellitus followed for 5 years (1). The was a 31% reduction in the rate of first laser treatments compared with the control group. The effect was mainly observed among participants with pre-existing retinopathy . Note that fenofibrate does its trick only in participants with pre-existing retinopathy. Thus, it reduces progression in those who already had retinopathy but DOES NOT prevent retinopathy in those who hasn’t (yet). FIELD also showed that fenofibrate significantly reduced secondary composite cardiovascular endpoint by 11% .
In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study (which is a substudy of the big ACCORD study), among 2856 participants with type 2 diabetes, significantly fenofibrate plus simvastatin reduced the rate of retinopathy progression by 40% compared with placebo plus simvastatin (3). Once again, the reduction was mostly seen in individuals with pre-existing mild retinopathy at baseline.
Both the FIELD and ACCORD Eye studies’ effect were independent of change in the lipid levels during the trial. It is thought that there must be other effects of the fenofibrate at work. Is it the other effects of the PPAR-α? So far, none has been demonstrated. A recent elegant study has shined some light on the matter from a different angle.
Diabetes and the bone marrow
Recently the bone marrow (BM) has emerged as a site of diabetic end-organ damage, and BM dysfunction accounts for the endothelial progenitor cells (EPC) reduction seen in diabetic patients (4). Interestingly, BM remodeling includes neurovascular changes and strongly resembles microangiopathy seen in the kidney and retina. EPCs arising from the bone marrow circulate in the bloodstream and home in to areas of injury to orchestrate vascular repair (Grant et al., 2002)(5). Mobilisation of EPC from the bone marrow occurs after activation of peripheral noradrenergic neurons and release of norepinephrine (NE), which suppresses osteoblast activity (Serre et al., 1999; Méndez-Ferrer et al., 2008) (6,7). The potential to form new blood vessels and repair damaged vessels depends on the EPCs’ ability to both leave the bone marrow and to migrate toward the site of angiogenesis. Decrease in circulating haematopoietic stem/progenitor cells (HSPCs) and EPCs, thus, reduce repair of injured retinal vessels in diabetics.
Baseline HSPCs and EPCs
Do levels of HSPCs and EPCs predict the progression of microangiopathy? Rigato et al (2015) showed reduced levels of circulating HSPCs predict subsequent worsening of microangiopathy (microalbuminuria and retinopathy) in patients with T2D over a time course of 3.9 years (8). They found that CD34+ and CD133+ were lower in patients with retinopathy or neuropathy than in those without. CD34+ were also lower in patients with asymptomatic atherosclerosis than in those without. Interestingly, they also found that reduction in CD34+ abolished the protective effects of ACE inhibitors/ARBs on urinary albumin excretion rate (UAER) progression.
A possible mechanism of benefit from fenofibrate?
Does fenofibrate increase HSPCs and EPCs and thence, reduce the progression? In a single-centre, phase IV, randomised, single-blind, placebo-controlled trial, 42 patients aged 18-70 years with diabetes (type 1 and 2) and any grade of retinopathy were recruited between August 2013 and March 2019 at the diabetes outpatient clinic of the University Hospital of Padova (Bonora et al 2021)(9).
Participants were randomised 1:1 to receive treatment with daily fenofibrate 145 mg or matching daily placebo for 12 weeks. Apart from the usual blood tests biochemical analysis, circulating HSPCs were measured using flow cytometry. Cells expressing CD34 and/or CD133 were defined as HSPCs, whereas co-expression of KDR was used to define EPCs.
Participants were on average 57.4 years old and had a diabetes duration of 18.2 years, a baseline HbA1c of 7.6% and an overall good control of concomitant risk factors. As for the retinopathy stage, 26 participants (63.4%) had non-proliferative retinopathy, 15 participants (36.6%) had proliferative retinopathy and 16 participants had concomitant macular oedema, with no difference between groups.
After 12 weeks, all three phenotypes of HSPCs (CD34+, CD133+ and CD34+/CD133+ cells) significantly increased in the fenofibrate group, while they non-significantly decreased in the placebo group. The effect on the HSPCs was unrelated to the changes in serum triglycerides, suggesting that non-lipid mechanisms may be involved. Systemic mediators of inflammation or HSPC traffic were not affected by fenofibrate and they detected no significant change in the expression of PPARA and PPAR-α target genes in peripheral blood mononuclear cells. The authors speculate that fenofibrate increased HSPCs through an action on the BM rather than on peripheral blood.
Since we know that low HSPCs can predict the progression of retinopathy, Bonora et al used the data to predict the effect of fenofibrate on the progression of retinopathy. Using complex mathematical modelling and calculation, they yielded an odd ratio (OR) of progression of 0.67 in the fenofibrate vs placebo group. Wow, this was pretty consistent with the OR of the FIELD and ACCORD-EYE trials!
Perhaps, increasing HSPCs with targeted therapy may slow diabetic micro- and macroangiopathy. That’s another angle to reduce diabetes related complications. In the meantime, if you have a patient with retinopathy of any grade, please ensure that they are commenced on fenofibrate (even though many will not qualify under the PBS for severe hypertriglyceridaemia). Further, these patients are likely to have high risks of cardiovascular events and it’s time to reassess their cardiovascular risks.
- Chew EY, AmbrosiusWT, DavisMD et al (2010) Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 363:233–244. https://doi.org/10.1056/NEJMoa1001288
- Keech A, Simes RJ, Barter P et al (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366:1849–1861. https://doi.org/10.1016/S0140-6736(05)67667-2
- Keech AC, Mitchell P, Summanen PA et al (2007) Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370:1687–1697. https://doi.org/10.1016/S0140-6736(07)61607-9
- Fadini GP, Ferraro F, Quaini F, Asahara T, Madeddu P. Concise review: diabetes, the bone marrow niche, and impaired vascular regeneration. Stem Cells Transl Med. 2014 Aug;3(8):949-57. doi:10.5966/sctm.2014-0052.
- Grant, M.B., W.S. May, S. Caballero, G.A. Brown, S.M. Guthrie, R.N. Mames, B.J. Byrne, T. Vaught, P.E. Spoerri, A.B. Peck, and E.W. Scott. 2002. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat. Med. 8:607–612. doi:10.1038/nm0602-607
- Serre, C.M., D. Farlay, P.D. Delmas, and C. Chenu. 1999. Evidence for a dense and intimate innervation of the bone tissue, including glutamate-containing fibers. Bone. 25:623–629. doi:10.1016/S8756-3282(99)00215-X
- Méndez-Ferrer, S., D. Lucas, M. Battista, and P.S. Frenette. 2008. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 452:442–447. doi:10.1038/nature06685
- Mauro Rigato, Cristina Bittante, Mattia Albiero, Angelo Avogaro, Gian Paolo Fadini, Circulating Progenitor Cell Count Predicts Microvascular Outcomes in Type 2 Diabetic Patients, The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 7, 1 July 2015, Pages 2666–2672, https://doi.org/10.1210/jc.2015-1687
- Bonora, B.M., Albiero, M., Morieri, M.L. et al. Fenofibrate increases circulating haematopoietic stem cells in people with diabetic retinopathy: a randomised, placebo-controlled trial. Diabetologia (2021). https://doi-org.ezproxy.uws.edu.au/10.1007/s00125-021-05532-1