Therapeutic Triangulation: The DME Treatment Revolution

Anti-VEGF medications, steroids and laser treatment offer a triad of effective options. What evidence guides selection?

Robert Murphy, CONTRIBUTING EDITOR

The past 12 years have witnessed a revolution in the treatment of diabetic macular edema (Figure 1). Until the turn of the millennium, laser therapy was the gold standard for DME treatment. Beginning around 2000, retinal specialists initiated the widespread use of intravitreal triamcinolone to reduce macular edema and improve vision in these patients. By the middle of the last decade, studies had emerged showing that intravitreal injections of anti-VEGF medications, such as bevacizumab and later ranibizumab, provided effective therapy with a benign safety profile.

Figure 1. Growing evidence suggests that combination therapies might be the best approach for DME.

Today, retinal specialists can avail themselves of all three treatments for patients with diffuse clinically significant diabetic macular edema. In recent years, anti-VEGF injections have become the preferred treatment of first choice for many clinicians, even as focal grid laser treatment and steroid injections are employed as options for sequential combination therapy. Many cases become a matter of trial and error, as individual patients may respond differently to one or another treatment regimen. No single therapeutic algorithm has emerged as an ideal all-purpose approach.

Each of the treatments has its advantages and drawbacks. Retinal specialists can therefore mix and match the treatment options to provide a therapeutic regimen best suited to the case at hand.

ANTI-VEGF MEDICATIONS

Abundant research has implicated vascular endothelial growth factor as the chief inciting cytokine responsible for diabetic macular edema. VEGF has been found to increase vascular permeability and thereby instigate the vessel leakage leading to edema. Thanks to their efficacy and lack of side effects, anti-VEGF medications have become the favored treatment of first choice for many retinal specialists.

“There has been published medical evidence to demonstrate that anti-VEGF therapy is superior to either focal grid laser therapy or intravitreal steroids for the treatment of center-involved diabetic macular edema,” says Diana Do, MD, an associate professor of ophthalmology at the Wilmer Eye Institute at the Johns Hopkins University School of Medicine. “With this growing medical evidence from phase 3 clinical trials, now retinal specialists and ophthalmologists have clear-cut evidence to use intravitreal anti-VEGF therapy in patients who come in with decreased vision and center-involved diabetic macular edema.”

A study conducted by the Diabetic Retinopathy Clinical Research Network and published in the June 2010 issue of Ophthalmology randomized 854 eyes with DME and visual acuity from 20/32 to 20/320 to receive 0.5 mg ranibizumab plus prompt laser (n=187), 0.5 mg ranibizumab plus deferred laser (n=188), 4 mg triamcinolone plus prompt laser (n=186), or sham injection plus prompt laser (n=293).¹ The one-year mean change in the visual acuity letter score from baseline was significantly greater in the ranibizumab-plus-prompt-laser group and the ranibizumab-plus-deferred-laser group, but not in the triamcinolone-plus-prompt-laser group, when compared with the sham-plus-prompt-laser group.

Navigated Laser Treatment Allows for Precise Application

The laser technology used to treat DME has been a mainstay in retina practices for years, and the recent development of so-called navigated retinal photocoagulation — integrating fluorescein imaging, image stabilization and tracking — might help to improve accuracy and safety, its proponents say. Marketed as Navilas, from OD-OS of Teltow, Germany, the system uses a computer screen to mark the planned treatment locations on a fluorescein or color image. The treatment plan is then registered to the live fundus image, allowing for more precise placement of the laser spots. “The laser is only going to fire where it's matched to the angiogram,” says Stephanie Lu, MD, a clinical researcher at the Gavin Herbert Eye Institute at the University of California, Irvine, which obtained the laser in April 2011. “So it's only going to fire at spots where it's preplanned on the picture.” This precise positioning allows for lower total energy delivery with less potential for collateral damage, Dr. Lu says. This accuracy means the surgeon can get closer to the foveal avascular zone than was feasible in the past. The Gavin Herbert Eye Institute is one of three US locations conducting small-scale pilot studies, along with the University of California, San Diego, and a private practice in Detroit. The treatment protocol calls for pretreatment with up to three bevacizumab injections before applying the laser. “So far, the results are pretty impressive,” Dr. Lu says. “We're not going to say this is going to replace all injections, but what we can say is that it's going to reduce the frequency of injections. In the long run, it will cut down on the cost of treatment.”

The RISE and RIDE studies conducted by researchers at the Wilmer Eye Institute likewise found favorable outcomes from the use of 0.3 mg or 0.5 mg intravitreal injections of ranibizumab compared with sham injections.² In the meantime, UK researchers participating in the BOLT study found that patients receiving intravitreal injections of bevacizumab over 12 months gained a median of eight ETDRS letters compared with a median loss of 0.5 letters among the laser group.³

“Anti-VEGF therapy is highly effective, and many would say it is the most effective [treatment],” says Carl Regillo, MD, director of the Retina Service at the Wills Eye Institute and professor of ophthalmology at Thomas Jefferson University. “The drawback is that it doesn't last very long — four to six weeks. Therefore, it requires many frequently performed injections, as many as eight or so in the first year, possibly up to six or so in the second year. So it is inconvenient and costly. Still, most clinicians consider it to be first-line therapy because it can get you your best vision. You can get the edema to go down and improve the vision very quickly and without side effects.”

TRIAMCINOLONE

Researchers and clinicians have found that intravitreal injections of Kenalog often work as well as anti-VEGF medications in terms of reduction of edema and improved vision. Steroids offer an advantage over anti-VEGF therapy in that their effect lasts longer, on average four to five months. Patients therefore require less frequent injections.

Steroids also wield a sort of shotgun effect, blasting away at all cytokines within reach, not just VEGF. “If you do assays of the vitreous in patients with diabetic macular edema, many cytokines are present,” says San Diego retinal specialist Paul Tornambe, MD, who also serves on the voluntary clinical faculty at the University of California, San Diego, Department of Family Practice and Preventive Medicine. “These include interleukin 6, interleukin 8 and MCP-1. VEGF inhibitors do not affect these cytokines. That's the reason why the VEGF inhibitors can be disappointing in diabetic macular edema. The only substance that does get to that full range of cytokines is a steroid. Steroids inhibit all those other cytokines as well as VEGF.”

Another means of delivering steroids intravitreally is the use of a sustained-release implant. Iluvien (fluocinolone acetonide) was recently approved in Europe, but was earlier denied FDA approval for DME. “It was a big surprise that Iluvien did not get FDA approval for treating DME,” Dr. Regillo says. “The safety profile was comparable to a 4 mg dose of triamcinolone, but the device gave us a duration of action of approximately three years. There are many patients that continue to have recurrences of significant macular edema and respond well to intraocular steroids for years. Iluvien would be a good option for these types of patients.”

Allergan's intravitreal implant Ozurdex (dexamethasone) has received FDA approval to treat macular edema following branch or central retinal vein occlusion, as well as noninfectious posterior-segment uveitis. The company is now looking at obtaining an additional indication for DME. “Ozurdex is likely to also play a role in DME treatment,” Dr. Regillo says. “Although it doesn't last much longer than a 2 mg or 4 mg dose of triamcinolone, it appears to have a lower rate of intraocular pressure elevation, and therefore may be preferred in some patients for that reason.”

But steroid treatment has its drawbacks. “It has the side effects of raising intraocular pressure,” Dr. Regillo says. “Thirty to 40 percent of patients will have some pressure rise, especially with 4 mg of triamcinolone, and that needs management. There is cost and inconvenience to manage elevated intraocular pressure and the danger of sustained pressure elevation if you can't control it.” Steroids are also notorious for hastening cataract progression.

Even so, many retina specialists include intravitreal triamcinolone injections among their options for sequential DME treatment, especially for those who respond inadequately to anti-VEGF injections or focal grid laser therapy.

LASER TREATMENT

Focal grid treatment with a green-wavelength laser can be especially effective in cases where the edema is mild and outside of the foveal center and vision is still good. “It has been proven to work, and was the original gold standard treatment for many, many years,” Dr. Regillo says. It also has a favorable side effect profile.

But it, too, has its drawbacks. “It is slow to work, and it doesn't work as well” as other treatment options, Dr. Regillo says. Patients will likely require multiple laser treatments over several years. “The more severe the edema, the less effective it tends to be,” Dr. Regillo says. “And people don't notice much visual improvement. Maybe after several treatments over many months, their vision will slowly improve.”

Dr. Tornambe advocates a different treatment approach: applying photocoagulation to ischemic areas of the peripheral retina, which he identifies as the main source of VEGF elaboration and subsequent vascular leakage in DME. “If you study DME eyes using widefield angiography, you see that blood vessels are leaking not only in the macula, but throughout the whole retina,” Dr. Tornambe says. “There is significant poor perfusion in the periphery. And I believe that if you're going to apply laser, the laser should be applied to the peripheral ischemic retina directed by widefield angiography. If you treat the peripheral ischemic retina with confluent tight laser applications, you will decrease the ischemic drive, which decreases or pre vents the cytokines from being released.” He couples this treatment with one or two anti-VEGF injections early on to counteract initial VEGF elaboration stemming from the laser treatment.

After using this treatment approach for more than a year, Dr. Tornambe is seeing good results. “I now have patients with more than a year of follow-up who had massive diabetic macular edema that responded to this treatment, and required a total of three or four injections throughout the entire year,” Dr. Tornambe says. “Several have had no injections for six months and appear stable.”

SEQUENTIAL COMBINATION TREATMENT

While all three of the main treatments for DME have their pros and cons, many patients may benefit from a sequence that combines the benefits that two or more have to offer. Often it's a matter of trial and error, mixing and matching to find the regimen best suited to the case at hand.

“Almost everyone starts with anti-VEGF, and will sometimes go to a steroid if they can't wean off the anti-VEGF treatment,” Dr. Regillo says. “So the first-line treatment is anti-VEGF followed by steroids for some people.” Of course, other regimens are popular as well, given the circumstances. “Laser is used if the edema is mild and outside the foveal center,” Dr. Regillo says. “You can treat the edema and get it to go away before it hits the fovea. We also tend to add laser later. So we'll start injecting drugs, usually anti-VEGF agents, and in order to minimize the number of treatments and to prevent recurrences, a lot of us will add focal laser later.”

What might prompt you to switch from one treatment to another? Dr. Regillo identifies two scenarios that may call for a change. “One would be a lack of good response, like incomplete resolution of the edema,” Dr. Regillo says. “Sometimes you'll inject bevacizumab and you won't see much happening, then you try something else and you figure out what works best.”

Another scenario is recurrence, which often happens. “If the edema keeps recurring, you might want to throw in a focal laser treatment, which has a more permanent effect,” Dr. Regillo says. “With the drugs, the effect tends to wear off and the edema comes back.” Having three effective options at your disposal allows you to try something else in the event that one treatment proves inadequate.

A DECADE OF SIGNIFICANT ADVANCES

In little more than a decade, retinal specialists have progressed from having a single therapeutic option for diffuse clinically significant diabetic macular edema (laser) to the present menu of three proven treatments. Says Dr. Regillo, “They all work, and we have a good feel for them because we've been using them with our patients for several years now.”

If this is what can happen over a 10- to 12-year period, who is to predict what clinical advances in DME treatment may follow in the decade to come? RP

REFERENCES

1. The Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010; 117:1064-1077.
2. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Feb 11 [Epub ahead of print].
3. Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010; 117:1078-1086.