What are the benefits and risks of steroid injections for treating diabetic macular edema, a complication of diabetes?

Why this question is important
Diabetes causes high levels of sugar in the blood. This can damage the small blood vessels at the back of the eye (the retina). If they leak, the central part of the retina (the macula) swells. This is called diabetic macular edema, and can cause blurred vision. If it is not treated, it can cause permanent vision loss.

One way to treat this is to inject steroids (anti-inflammatory medicines) into the eye. We reviewed the research evidence to compare the benefits and risks of this treatment against no treatment or other treatments.

How we identified and assessed the evidence
We searched for all relevant studies in the medical literature, compared their results, and summarized the evidence. We assessed how certain the evidence was for each finding, based on factors such as how well studies were conducted, study sizes, or consistency of findings across studies. We categorized the evidence as being of very low-, low-, moderate-, or high-certainty.

What we found
We identified 10 studies on 4348 people with diabetic macular edema. Participants were followed for nine to 36 months. The studies investigated three different injected steroids: dexamethasone, fluocinolone, and triamcinolone. Six studies were funded by pharmaceutical manufacturers.

Benefits (measured 12 or 24 months after treatment)

Compared to a sham treatment:

• Dexamethasone and fluocinolone probably improve visual sharpness and reduce thickness of the retina more; triamcinolone may also do this.

• It is probable that more people’s vision improves by three lines or more on a vision chart with fluocinolone. Evidence is insufficient to tell whether dexamethasone or triamcinolone has the same effect.

Compared to antiangiogenics (medicines that prevent new blood vessels forming behind the retina):

• Dexamethasone probably improves visual sharpness similarly or slightly less but may reduce thickness of the retina slightly more. Triamcinolone may improve visual sharpness less too; we do not know how it affects thickness of the retina because the evidence is of very low-certainty.

• We cannot tell whether more people’s vision improves by three lines or more on a vision chart with dexamethasone or triamcinolone. This is because the evidence on dexamethasone is inconsistent and of low-certainty, and no studies on triamcinolone evaluated this.

Compared to laser therapy:

• Triamcinolone may make little or no difference to whether people’s vision improves by three lines or more on a vision chart.

• We do not know whether triamcinolone increases visual sharpness or reduces thickness of the retina more due to insufficient evidence.

Risks (measured nine to 36 months after treatment)

Compared to a sham treatment:

• It is probable that cataracts progress in more people with dexamethasone or fluocinolone; cataract may be more likely with triamcinolone too.

• It is probable that more people treated with dexamethasone or fluocinolone need drops that lower eye pressure. The evidence is too imprecise to show if triamcinolone affects the need for such drops.

• Fluocinolone may increase the risk of needing surgery for glaucoma (optic nerve damage caused by high pressure in the eye). There is insufficient evidence to show if dexamethasone or triamcinolone affects the need for glaucoma surgery.

Compared to antiangiogenics:

• Cataract progression and the need for pressure-lowering eye drops is probably greater with dexamethasone.

•We do not know if dexamethasone affects the need for glaucoma surgery because the evidence is poor and imprecise.

•There is insufficient evidence to show if triamcinolone causes more adverse effects.

Compared to laser therapy:

• Cataract progression and the need for pressure-lowering eye drops is probably greater with triamcinolone.

• The evidence is too imprecise to show how triamcinolone affects the need for glaucoma surgery.

What this means
Evidence of low- to moderate-certainty suggests that:

- steroids may be, or probably are, more effective than a sham treatment;

- steroids may be, or probably are, less effective at improving visual sharpness than antiangiogenics;

- steroids may, or probably, increase the risk of cataract progression and elevated eye pressure.

How up-to-date is the review?
The evidence in this Cochrane Review is current to 15 May 2019.

Authors' conclusions: 

Intravitreal steroids may improve vision in people with DME compared to sham or control. Effects were small, about one line of vision or less in most comparisons. More evidence is available for dexamethasone or fluocinolone implants when compared to sham, and the evidence is limited and inconsistent for the comparison of dexamethasone with antiVEGF treatment. Any benefits should be weighed against IOP elevation, the use of IOP-lowering medication and, in phakic patients, the progression of cataract. The need for glaucoma surgery is also increased, but remains rare.

Read the full abstract...
Background: 

Diabetic macular edema (DME) is secondary to leakage from diseased retinal capillaries with thickening of central retina, and is an important cause of poor central visual acuity in people with diabetic retinopathy. Intravitreal steroids have been used to reduce retinal thickness and improve vision in people with DME.

Objectives: 

To assess the effectiveness and safety of intravitreal steroid therapy compared with other treatments for DME.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase on 15 May, 2019. We also searched reference lists, Science Citation Index, conference proceedings, and relevant trial registers. We conducted a top up search on 21 October, 2020.

Selection criteria: 

We included randomized controlled trials that evaluated any type of intravitreal steroids as monotherapy against any other intervention (e.g. observation, laser photocoagulation, anti-vascular endothelial growth factor (antiVEGF) for DME.

Data collection and analysis: 

Two review authors independently assessed study eligibility and risk of bias and extracted data. Where appropriate, we performed meta-analyses.

Main results: 

We included 10 trials (4348 participants, 4505 eyes). These trials compared intravitreal steroid therapies versus other treatments, including intravitreal antiVEGF therapy, laser photocoagulation, and sham injection. Most trials had an overall unclear or high risk of bias.

One trial (701 eyes ) compared intravitreal dexamethasone implant 0.7mg with sham. We found moderate-certainty evidence that dexamethasone leads to slightly more improvement of visual acuity than sham at 12 months (mean difference [MD] −0.08 logMAR, 95% confidence interval [CI] −0.12 to −0.05 logMAR). Regarding improvement of three or more lines of visual acuity, there was moderate-certainty evidence in favor of dexamethasone at 12 months, but the CI covered the null value (risk ratio (RR) 1.39, 95% CI 0.91 to 2.12). Regarding adverse events, dexamethasone increased by about four times the risk of cataract progression and the risk of using intraocular pressure (IOP)-lowering medications compared to sham (RR 3.89, 95% CI 2.75 to 5.50 and RR 4.54, 95% CI 3.19 to 6.46, respectively; moderate-certainty evidence); about 4 in 10 participants treated with dexamethasone needed IOP-lowering medications.

Two trials (451 eyes) compared intravitreal dexamethasone implant 0.7mg with intravitreal antiVEGF (bevacizumab and ranibizumab). There was moderate-certainty evidence that visual acuity improved slightly less with dexamethasone compared with antiVEGF at 12 months (MD 0.07 logMAR, 95% CI 0.04 to 0.09 logMAR; 2 trials; 451 participants/eyes; I2 = 0%). The RR of gain of three or more lines of visual acuity was inconsistent between trials, with one trial finding no evidence of a difference between dexamethasone and bevacizumab at 12 months (RR 0.99, 95% CI 0.70 to 1.40; 1 trial; 88 eyes), and the other, larger trial finding the chances of vision gain were half with dexamethasone compared with ranibizumab (RR 0.50, 95% CI 0.32 to 0.79; 1 trial; 432 participants). The certainty of evidence was low. Cataract progression and the need for IOP-lowering medications increased more than 4 times with dexamethasone implant compared to antiVEGF (moderate-certainty evidence).

One trial (560 eyes) compared intravitreal fluocinolone implant 0.19mg with sham. There was moderate-certainty evidence that visual acuity improved slightly more with fluocinolone at 12 months (MD −0.04 logMAR, 95% CI −0.06 to −0.01 logMAR). There was moderate-certainty evidence that an improvement in visual acuity of three or more lines was more common with fluocinolone than with sham at 12 months (RR 1.79, 95% CI 1.16 to 2.78). Fluocinolone also increased the risk of cataract progression (RR 1.63, 95% CI 1.35 to 1.97; participants = 335; moderate-certainty evidence), which occurred in about 8 in 10 participants, and the use of IOP-lowering medications (RR 2.72, 95% CI 1.87 to 3.98; participants = 558; moderate-certainty evidence), which were needed in 2 to 3 out of 10 participants.

One small trial with 43 participants (69 eyes) compared intravitreal triamcinolone acetonide injection 4 mg with sham. There may be a benefit in visual acuity at 24 months (MD −0.11 logMAR, 95% CI −0.20 to −0.03 logMAR), but the certainty of evidence is low. Differences in adverse effects were poorly reported in this trial.

Two trials (615 eyes) compared intravitreal triamcinolone acetonide injection 4mg with laser photocoagulation and reached discordant results. The smaller trial (31 eyes followed up to 9 months) found more visual acuity improvement with triamcinolone (MD −0.18 logMAR, 95% CI −0.29 to −0.07 logMAR), but a larger, multicenter trial (584 eyes, 12-month follow-up) found no evidence of a difference regarding change in visual acuity (MD 0.02 logMAR, 95% CI -0.03 to 0.07 logMAR) or gain of three or more lines of visual acuity (RR 0.85, 95% CI 0.55 to 1.30) (overall low-certainty evidence). Cataract progression was about three times more likely (RR 2.68, 95% CI 2.21 to 3.24; moderate-certainty evidence) and the use of IOP-lowering medications was about four times more likely (RR 3.92, 95% CI 2.59 to 5.96; participants = 627; studies = 2; I2 = 0%; moderate-certainty evidence) with triamcinolone. About 1 in 3 participants needed IOP-lowering medication.

One small trial (30 eyes) compared intravitreal triamcinolone acetonide injection 4mg with intravitreal antiVEGF (bevacizumab or ranibizumab). Visual acuity may be worse with triamcinolone at 12 months (MD 0.18 logMAR, 95% CI 0.10 to 0.26 logMAR); the certainty of evidence is low. Adverse effects were poorly reported in this trial.

Four trials reported data on pseudophakic participants, for whom cataract is not a concern. These trials found no decrease in visual acuity in the second treatment year due to cataract progression.

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