Prevention of Diabetic Retinopathy

The risk of diabetic retinopathy increases with duration of diabetes mellitus. The treatment offered by ophthalmologists usually addresses ocular complications occurring in advanced stages, i.e. neovascularisation or diabetic macular edema. There are however interventions that may delay or even prevent the development of such complications. A systematic review and meta-analysis encouragingly suggests that in recent decades progression to advanced diabetic retinopathy has fallen, quite possibly due to improved care and management of these risk factors [1]*. Screening is designed to allow early detection and timely treatment of sight threatening retinopathy. Screening also may also encourage patients with diabetes and no visual symptoms to reflect on the risk to their vision and consider what their modifiable risk factors might be. The UK’s diabetic eye screening programme has offered screening to 86% of eligible patients, and there is evidence that it is effective in reducing the rate of blindness [2]*. Delay in screening patients newly diagnosed with type 2 diabetes increases the rate of referable retinopathy detected [3]*. Retinopathy screening appears to be cost-effective [4]*.

*[1] [2] [3] [4]

Background

It has been accepted wisdom since the UK Prospective Diabetes Study (UKPDS) [5] of type 2 diabetes and Diabetes Control and Complications Trial (DCCT) [6] of type 1 diabetes that intensive control of blood sugars and blood pressure influence the incidence and progression of diabetic retinopathy.

For example in the DCCT patients were randomized to either an ‘intensively treated group’ or a ‘conventionally treated group’ based on blood glucose control. In the former the mean HbA1c over the study period was 7.2%, while that of the conventionally treated group was 9.1%.

DCCT was terminated after a mean of 6.5 years follow up (range 3 to 9 years). In those without signs of retinopathy at baseline, there was no difference in incidence of retinopathy until 3y, when the intensively treated participants began to show more favorable outcomes: at the end of the study there was a 76% (95% confidence intervals 62-85%) reduction in the incidence of retinopathy in those in the intensively treated group compared to those conventionally treated. In those with mild to moderate retinopathy at baseline, the intensively treated group experienced greater progression for the first year, but at 3y began to do better: at the study end there was a 54% (95% confidence intervals 39-66%) reduction in risk or progression of retinopathy if intensively than if conventionally treated, and a significantly (p=0.002) reduced risk of needing laser photocoagulation.

Glucose Control

Although targets for glycemic control are often set by national medical bodies, in the DCCT no specific glycemic target was suggested not only as there was a continuous relationship between risk of retinopathy progression and HbA1c, but also as other factors influence the practicality of intensive monitoring and control, not least the risk of hypoglycemic events.

Interestingly when DCCT participants were followed-up 4y later, and even though glycemic control was not significantly different (p<0.001) in all subjects regardless of which DCCT group they had been in, the benefits of prior tight control during the DCCT appeared to persist (p<0.001) [7]. This finding was also apparent in the UKPDS follow-up study, and was described as a ‘legacy’ or ‘memory’ effect [8]. Conscientious glycemic control early in the course of a patient’s DM therefore has a lasting physiological effect.

Blood Pressure Control

Intensive control of blood pressure brings an independent and additive benefit to that of tight glucose control. For example in the UKPDS the risk reduction for progression of DR if BP was intensively controlled was 34% (95% confidence intervals 11-50%).

However more recently the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [9] investigated the effect of systemic factors on the incidence of cardiovascular events in patients with type 2 diabetes with established cardiovascular disease or cardiovascular risk factors. A sub-study, “ACCORD-Eye”, focused on progression of retinopathy, defined as a three step-worsening (as graded by the Early Treatment of Diabetic Retinopathy Study (ETDRS) grades), or need for laser photocoagulation or vitrectomy.

Progression was found to be significantly less frequent in those with better glycemic control (p=0.003) and in those given fenofibrate compared to those given placebo (p=0.006), but not in those with better blood pressure control (p=0.3). The lack of benefit of lowering blood pressure was thought to be due to a floor effect, in other words as the mean systolic blood pressure in the group in which blood pressure was not intensively controlled was 133mmHg, there was no additional benefit beyond this level.

ACCORD however delivered other notes of caution. Firstly in the group in which glycemic control was intense, the rate of hypoglycemia requiring third party assistance rose from 3.5% to 10.5%. Secondly intensive glycemic control was associated with an increased mortality, mainly from macrovascular causes, from 4 to 5%: it was this unexpected and as yet unexplained finding that resulted in the pertinent intervention arm being stopped early at 3.5y. Less strict blood glucose targets may be appropriate in those with established cardiovascular disease.

Smoking Cessation

Although it is common practice for ophthalmologists to advise their diabetic patients not to smoke, no association of smoking and retinopathy has been found in population-based studies from the US [10] and Denmark [11], or in studies based on clinic patients [12]. Nevertheless patients attending for monitoring or management of retinopathy should be encouraged to stop smoking, not only as it is an undisputed risk factor for cardiovascular disease [10], but also because smoking was associated with significantly increased risk of severe hypoglycemia in a study on patients with type 1 diabetes after correction for potential confounding factors [13].

Drug Therapy

Several medications are worth considering in the context of retinopathy prevention, such as lipid lowering agents. Higher LDL cholesterol and higher total to HDL cholesterol ratio were associated with increased risk of clinically significant diabetic macular edema, after controlling for age, sex, smoking, duration of diabetes and HbA1c in an analysis of DCCT participants [14], though high cholesterol was an exclusion criterion, and participants may not have been representative of patients attending clinics.

The Steno-2 trial randomized 160 participants to a multifactorial intervention, including advice on diet, exercise and smoking, and intensive control of blood glucose, blood pressure and lipids, or non-intensive control of these parameters. At four years relative risk of developing retinopathy was significantly lower in the intensively treated group (p=0.02) [15], while at eight years the need for retinal photocoagulation was significantly (p=0.02) less [16]. Thus evidence suggests that patients should be told to have their lipid profile checked and managed as appropriate.

Fenofibrate is licensed for the treatment of dyslipidemia. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study enrolled participants with well controlled type 2 diabetes to investigate the tolerability and efficacy of fenofibrate [17]. Participants were randomized to receive 200mg daily of fenofibrate, or placebo. Fenofibrate led to a statistically significant reduction in the risk of needing a first retinal laser treatment for macular edema (P=0.002) and for proliferative retinopathy (p=0.015) at 5y, after correction for other factors which may have predicted the need for laser.

There was a 64% reduction in the “occurrence of macular edema as judged by photography”. There were no significant safety concerns with fenofibrate. Furthermore statins were commenced more often in the placebo group, and there was no significant difference in lipid levels between treated and placebo groups. The mechanism of fenofibrate on diabetic macular edema is unclear, but it has anti-apoptotic, anti-inflammatory, anti-oxidative effects that may be pertinent.

Although encouraging, the FIELD study had retinopathy outcomes as tertiary outcomes, and some have raised concerns about unmeasured confounding factors. The ACCORD study also examined the potential role of systemic factors on retinopathy [9]. In an ACCORD-Eyes sub study there was a 40% reduction in the odds ratio of progression of retinopathy and maculopathy when fenofibrate was added to simvastatin compared to simvastatin used alone. It was suggested that fenofibrate should be used when there is “preproliferative diabetic retinopathy and/or macular edema or when there is early diabetic retinopathy in the only or best eye” [18]. A randomized study on fenofibrate for diabetic macular edema with ocular coherence tomography end-points is planned (see: clinicaltrials.gov).

Renin-angiotensin system inhibitors are central to the treatment of hypertension, but it has been suggested that renin-angiotensin inhibition may have beneficial effects on diabetic retinopathy independently of anti-hypertensive actions. Renin and ACE receptors are present in retinal and choroidal vessels, and intravitreal levels of prorenin are increased in retinopathy and correlate with its severity [19]. In ‘EUCLID’ (EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus) normotensive patients with type 1 diabetes, and little or no retinopathy were randomized to placebo or lisinopril [20]. Retinal photographs were taken at baseline and at 2 years: retinopathy was less likely to progress in those on lisinopril.

Although glycemic control during the study period was controlled for, at baseline the lisinopril group had a significantly lower HbA1c than the placebo group. Another study on patients with type 1 diabetes, but without hypertension or renal disease, randomized participants to enalapril, losartan or placebo [21]. Renin-angiotensin blockade with either agent significantly reduced retinopathy progression after 5y after adjustment for reductions in blood pressure, though there was no evidence of benefit in slowing nephropathy.

The DIRECT (Diabetic Retinopathy Candesartan Trials) studies were powered primarily to investigate the effect of candesartan on retinopathy in patients with no hypertension or nephropathy, who either had no signs of retinopathy and type 1 diabetes (‘DIRECT-Prevent 1’) [22], or had signs of retinopathy and type 1 diabetes (”DIRECT-Protect 1’) [22] or type 2 diabetes (”DIRECT-Protect 2’) [23].

In the type 1 diabetes cohort, candesartan reduced (p=0.034) the proportion experiencing a 3-step decline in retinopathy level from 16 to 10.5%, after adjusting for blood pressure, though this emerged from post hoc analysis. In the type 2 diabetic cohort candesartan led to significantly (p<0.009) greater regression of mild retinopathy but had no significant effect on moderate or worse retinopathy or on diabetic macular edema. It is worth noting that 28% of subjects in the placebo arm of this cohort started a renin-angiotensin blocking agent during the trial, which would be expected to dampen any differences between treatment and placebo groups.

Candesartan was well tolerated in both DIRECT studies. The practical import of these findings has yet to be established for retinopathy, but its suggested that renin-angiotensin blockers be considered in patients who have had type 1 diabetes for over 6 years, or type 2 patient with early signs of retinopathy, particularly if hypertension or diabetic nephropathy are present [24].

Glitazones have several actions such as enhancing insulin sensitivity in muscle and adipose tissue and inhibiting hepatic gluconeogenesis, but concerns have arisen over side effects of some agents, including fluid retention. It is hypothesized that glitazones might therefore promote diabetic macular edema. An uncontrolled case series described worsening of macular edema in association with starting a glitazone, and stopping the agent with resolution of the edema [25]. In a large retrospective study based on an electronic primary care database, glitazone use was associated with an increased risk of DME after adjustment for potentially confounding factors [26].

However association does not prove causation, and studies have not provided consistent results. A retrospective review of 124 patients on rosiglitazone who had retinopathy matched with 158 others not on a glitazone and found no difference in the incidence of macular edema over 3y: in fact there was a significantly lower rate of progression of retinopathy in those on the glitazone [27].

In the ACCORD-Eye study, 6875 eyes were photographed. In 1377 eyes, the patient was on a glitazone [28]. There was no association between glitazone use and macular edema at baseline, although methodological problems included the unknown duration of glitazone use prior to baseline, and uncertainty about whether photographs were a sensitive enough means to identify macular edema. In practice, if a patient with diabetic macular edema is taking a glitazone and not responding to treatment and they are on a glitazone, it may be worth of stopping the drug.

Physicians in primary and secondary care, and ophthalmologists, should consider the potential ocular and visual benefits of addressing systemic issues and reviewing medication use.

References

  1. ^ Wong TY, Mwamburi M, Klein R, Larsen M, Flynn H, Hernandez-Medina M, et al. Rates of progression in diabetic retinopathy during different time periods: a systematic review and meta-analysis. Diabetes Care. 2009;32(12):2307-13.

  2. ^ Papavasileiou E, Dereklis D, Oikonomidis P, Grixti A, Vineeth Kumar B, Prasad S. An effective programme to systematic diabetic retinopathy screening in order to reduce diabetic retinopathy blindness. Hell J Nucl Med. 2014;17 Suppl 1:30-4.

  3. ^ Scanlon PH, Aldington SJ, Stratton IM. Delay in diabetic retinopathy screening increases the rate of detection of referable diabetic retinopathy. Diabet Med. 2013.

  4. ^ James M, Turner DA, Broadbent DM, Vora J, Harding SP. Cost effectiveness analysis of screening for sight threatening diabetic eye disease. Bmj. 2000;320(7250):1627-31.

  5. ^ Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. Bmj. 1998;317(7160):703-13.

  6. ^ The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. The New England journal of medicine. 1993;329(14):977-86.

  7. ^ Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. The New England journal of medicine. 2000;342(6):381-9.

  8. ^ Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. The New England journal of medicine. 2008;359(15):1577-89.

  9. ^ Group AS, Group AES, Chew EY, Ambrosius WT, Davis MD, Danis RP, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. The New England journal of medicine. 2010;363(3):233-44.

  10. ^ Moss SE, Klein R, Klein BE. Cigarette smoking and ten-year progression of diabetic retinopathy. Ophthalmology. 1996;103(9):1438-42.

  11. ^ Gaedt Thorlund M, Borg Madsen M, Green A, Sjolie AK, Grauslund J. Is smoking a risk factor for proliferative diabetic retinopathy in type 1 diabetes? Ophthalmologica. 2013;230(1):50-4.

  12. ^ Lombrail P, Passa P, Thibult N, Eschwege E, Canivet J. [Prevalence of smoking among diabetics and influence of tobacco on diabetic retinopathy]. Presse Med. 1983;12(42):2677-9.

  13. ^ Hirai FE, Moss SE, Klein BE, Klein R. Severe hypoglycemia and smoking in a long-term type 1 diabetic population: Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes care. 2007;30(6):1437-41.

  14. ^ Miljanovic B, Glynn RJ, Nathan DM, Manson JE, Schaumberg DA. A prospective study of serum lipids and risk of diabetic macular edema in type 1 diabetes. Diabetes. 2004;53(11):2883-92.

  15. ^ Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. The New England journal of medicine. 2003;348(5):383-93.

  16. ^ Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. The New England journal of medicine. 2008;358(6):580-91.

  17. ^ Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007;370(9600):1687-97.

  18. ^ Wright AD, Dodson PM. Medical management of diabetic retinopathy: fenofibrate and ACCORD Eye studies. Eye. 2011;25(7):843-9.

  19. ^ Yokota H, Mori F, Kai K, Nagaoka T, Izumi N, Takahashi A, et al. Serum prorenin levels and diabetic retinopathy in type 2 diabetes: new method to measure serum level of prorenin using antibody activating direct kinetic assay. Br J Ophthalmol. 2005;89(7):871-3.

  20. ^ Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet. 1998;351(9095):28-31.

  21. ^ Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. The New England journal of medicine. 2009;361(1):40-51.

  22. ^ Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet. 2008;372(9647):1394-402.

  23. ^ Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet. 2008;372(9647):1385-93.

  24. ^ Wright AD, Dodson PM. Diabetic retinopathy and blockade of the renin-angiotensin system: new data from the DIRECT study programme. Eye. 2010;24(1):1-6.

  25. ^ Ryan EH, Jr., Han DP, Ramsay RC, Cantrill HL, Bennett SR, Dev S, et al. Diabetic macular edema associated with glitazone use. Retina. 2006;26(5):562-70.

  26. ^ Idris I, Warren G, Donnelly R. Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes. Arch Intern Med. 2012;172(13):1005-11.

  27. ^ Shen LQ, Child A, Weber GM, Folkman J, Aiello LP. Rosiglitazone and delayed onset of proliferative diabetic retinopathy. Arch Ophthalmol. 2008;126(6):793-9.

  28. ^ Ambrosius WT, Danis RP, Goff DC, Jr., Greven CM, Gerstein HC, Cohen RM, et al. Lack of association between thiazolidinediones and macular edema in type 2 diabetes: the ACCORD eye substudy. Archives of ophthalmology. 2010;128(3):312-8.

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