Ranibizumab and aflibercept, used to treat vision loss from diabetic macular edema, and approximately 20 to 30 times more expensive than bevacizumab, are not cost-effective for treatment of DME compared to bevacizumab unless their prices decrease substantially, according to a study published online by JAMA Ophthalmology.

The anti-vascular endothelial growth factor drugs have revolutionized DME treatment. A recent randomized clinical trial comparing anti-VEGF agents for patients with decreased vision from DME found that at one year aflibercept (2 mg) achieved better visual outcomes than repackaged (compounded) bevacizumab (1.25 mg) or ranibizumab (0.3 mg); the worse the starting vision, the greater the treatment benefit with aflibercept.

These agents also vary substantially in cost. On the basis of 2015 costs, aflibercept was $1,850, ranibizumab, $1,170, and repackaged (compounded) bevacizumab, approximately $60 per dose. Considering that these medicines may be given nine to 11 times in the first year of treatment and, on average, 17 times during five years, total costs can be substantial. In 2010, when these intravitreous agents were being used predominantly for age-related macular degeneration, ophthalmologic use of VEGF therapy cost approximately $2 billion or one-sixth of the entire Medicare Part B drug budget. In 2013, Medicare Part B expenditures for aflibercept and ranibizumab alone totaled $2.5 billion.

Adam R. Glassman, of the Jaeb Center for Health Research, Tampa, Fla., and colleagues examined the incremental cost-effectiveness ratios (ICERs) of aflibercept, bevacizumab and ranibizumab for the treatment of DME with an analysis of efficacy, safety and resource utilization data at one-year follow-up from the Diabetic Retinopathy Clinical Research Network Comparative Effectiveness Trial. The researchers determined the ICERs for all trial participants and subgroups with baseline vision of approximate Snellen equivalent 20/32 to 20/40 and baseline vision of approximate Snellen equivalent 20/50 or worse. One-year trial data were used to calculate cost-effectiveness for one year for the three anti-VEGF agents; mathematical modeling was then used to project 10-year cost-effectiveness results.

The study included 624 participants; 209 in the aflibercept group, 207 in the bevacizumab group and 208 in the ranibizumab group. The researchers found that in eyes with visual acuities of 20/50 or worse because of DME, aflibercept produced greater average VA gains compared with bevacizumab or ranibizumab. The analysis suggested that the VA benefits of aflibercept translate into modest quality-of-life improvements, but at a high cost relative to bevacizumab, with the ICERs substantially higher than the thresholds per quality-adjusted life-year frequently cited in cost-effectiveness literature and U.S. guidelines. The authors add that it is unlikely that any realistic differences in VA achieved with the three agents during years two to 10 (in the range of changes seen in prior studies) would alter their relative cost-effectiveness.

In eyes with decreased vision from DME, treatment costs of aflibercept and ranibizumab would need to decrease by 69 percent and 80 percent, respectively, to reach a cost-effectiveness threshold of $100,000 per QALY compared with bevacizumab during a 10-year horizon.

“From a societal perspective, bevacizumab as first-line therapy for DME would confer the greatest value, along with substantial cost savings vs. the other agents. These results highlight the challenges that physicians, patients and policymakers face when safety and efficacy results are at odds with cost-effectiveness results,” the researchers write.

A1C Control Shows Major DR Benefit
People with type 2 diabetes who intensively controlled their blood sugar level during the landmark Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial Eye Study were found to have cut their risk of diabetic retinopathy in half in a follow-up analysis conducted four years after stopping intensive therapy. Investigators who led the ACCORD Follow-on Eye Study (ACCORDION) announced the results at the American Diabetes Association annual meeting.

“This study sends a powerful message to people with type 2 diabetes who worry about losing vision,” said Emily Chew, MD, deputy director of the NEI Division of Epidemiology and Clinical Applications and lead author of the NEI-supported study, published online in Diabetes Care. “Well-controlled glycemia has a positive, measurable and lasting effect on eye health.”

ACCORDION is a follow-up assessment of diabetic retinopathy progression in 1,310 people who participated in ACCORD, which tested three treatment strategies to reduce the risk of cardiovascular disease among people with long-standing type 2 diabetes. ACCORD tested maintaining near-normal blood sugar levels (intensive glycemic control); improving blood lipid levels, such as lowering LDL cholesterol and triglycerides and raising HDL cholesterol; and lowering blood pressure.

The treatment phase of the glycemic control portion of ACCORD had been planned to last 5.6 years but was stopped at 3.5 years due to an increase in death among participants in the intensive glycemic control group. The blood pressure and blood lipid portions of ACCORD continued. Tight control successfully reduced glycemia to an average 6.4 percent A1C compared to 7.7 percent among participants on standard glycemic control therapy.

Although it failed to reduce cardiovascular disease risk, such as heart attack and stroke, the researchers found that the therapy had cut retinopathy progression by about one-third by the end of ACCORD. Investigators considered progression to have occurred if a participant required laser surgery for diabetic retinopathy, required a vitrectomy or advanced three or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale. The scale uses photographs of the retina to rate disease severity from 1 (no disease) to 17 (high-risk for progression in both eyes).

ACCORDION re-assessed diabetic retinopathy about four years after the intensive glycemic control portion of the study had ended, eight years after enrollment in ACCORD. By then, average A1C was nearly the same: 7.8 percent for the intensive therapy group and 7.9 percent for the standard therapy group. However, diabetic retinopathy had advanced in only 5.8 percent of participants in the intensive therapy group since enrollment in ACCORD, compared to 12.7 percent in the standard therapy group.

“Despite this equalization of glycemic control in the two groups, there continued to be an approximately 50-percent risk reduction of further retinopathy progression, a phenomenon termed metabolic memory,” said Frederick L. Ferris III, MD, NEI clinical director, who was not involved in the study.

Other clinical trials have reported the phenomenon, also known as the legacy effect. Participants with type 1 diabetes who received intensive glycemic therapy in the 10-year-long Diabetes Control and Complications Trial on average had 50-percent less progression of diabetic retinopathy three decades later. A similar trend was seen in the United Kingdom Prospective Diabetes Project, a study of people with newly diagnosed type 2 diabetes.

Results from ACCORDION suggest that lowering blood glucose can reduce progression of retinal disease relatively late in the course of type 2 diabetes and that even short-term changes in glucose have an effect. The findings add to mounting evidence that tight glycemic control has positive, long-lasting effects on small blood vessels. Other follow-up studies of ACCORD participants have observed a legacy effect similar to ACCORDION in kidney and peripheral nerve health, which also involve small blood vessels. But the benefits of intensive glycemic therapy must be weighed against the potential risks—most notably the increased risk of death observed in ACCORD. Investigators have been unable to determine a cause for the increase, which was not seen in other trials.

Results also point to a possible role for ongoing use of fenofibrate to treat diabetic retinopathy, if taken regularly. The blood lipid and blood pressure portions of ACCORD concluded at 5.6 years. Neither strategy reduced cardiovascular disease. However, fenofibrate, a drug that raises HDL cholesterol, decreased diabetic retinopathy progression by about one-third during ACCORD. ACCORDION investigators found fenofibrate had no lasting benefit three years after the drug was discontinued.

But based on ACCORD findings, fenofibrate might be worth taking to control diabetic retinopathy progression. Other countries, including Australia, have approved fenofibrate for treating diabetic retinopathy but not the United States, said Dr. Chew. The NEI-funded Diabetic Retinopathy Clinical Research Network is currently planning a clinical trial to further explore ongoing use of fenofibrate to control diabetic retinopathy.  REVIEW