Candesartan May Lessen Retinopathy
Three studies in The Lancet analyzed the action of the angiotensin receptor antagonist candesartan on prevention and treatment of diabetic retinopathy. Although the studies suggest overall beneficial effects of candesartan in reducing retinopathy in both type 1 and type 2 diabetes, the findings were mixed, since some of the prespecified endpoints were not met.
However, the authors suggest that the results indicate a possible role for candesartan in treating patients with type 2 diabetes with established retinopathy and for preventing retinopathy in patients with type 1 diabetes who have poorly controlled blood glucose levels.
“The studies show consistent findings in the overall change in retinopathy, favoring improvement and less progression of retinopathy in patients on active treatment,” said author Anne Katrin Sjølie, MD, clinical professor of ophthalmology at Odense University Hospital, Denmark. Dr. Sjølie noted that candesartan’s beneficial effects could result from the inhibition of the upregulation of the renin-angiotensin system in the eyes of patients with diabetes. “It’s also known that blood pressure is important for the development and worsening of retinopathy, and candesartan is a blood pressure–lowering agent as well,” she said.
The three studies published in two papers in The Lancet make up the Diabetic Retinopathy Candesartan Trials (DIRECT). In these studies, 5,231 patients with type 1 or type 2 diabetes from 309 medical centers worldwide were randomized to daily placebo or 32 mg of candesartan. Patients were followed for four years.
In DIRECT-Prevent 1 and DIRECT-Protect 1, Nish Chaturvedi, MD, and colleagues studied the effects of candesartan on patients with type 1 diabetes who were normotensive and had no diabetic retinopathy at baseline, and on type 1 diabetics with existing retinopathy.1
In DIRECT-Prevent 1, when incidence was defined as progression of at least two steps on the ETDRS (Early Treatment Diabetic Retinopathy Study) scale, treatment resulted in a relative risk reduction of 18 percent for type 1 diabetics without retinopathy at baseline. This beneficial effect was attenuated when the data were adjusted for variables such as duration of diabetes and blood pressure measurements; there was borderline statistical significance between the placebo and treatment groups. When incidence was defined as a three-step (or greater) progression on the ETDRS scale, patients on candesartan experienced a 35 percent relative risk reduction for retinopathy, which remained significant even after adjustment for baseline patient characteristics.
In DIRECT-Protect 1, in which type 1 diabetics with existing retinopathy were randomly assigned to placebo or candesartan, the primary endpoint—progression of retinopathy—occurred equally in both placebo and treatment groups.
In another study, Dr. Sjølie and colleagues asked whether candesartan could slow the progression and induce regression of retinopathy in type 2 diabetics with mild to moderately severe retinopathy.2 The results showed that the drug reduced the progression of retinopathy (defined as progression by three steps or more on the ETDRS scale) by 13 percent compared with placebo, but the difference between the two groups was not significant. Yet candesartan was associated with a 34 percent increase in the relative chance of regression of retinopathy (defined as a reduction of at least two steps sustained at two consecutive follow-up visits or three or more steps on the ETDRS scale from baseline to any follow-up visit). This finding was significant in patients with mild retinopathy. The finding was not attenuated by adjustment for baseline patient characteristics.
In all the studies, adverse events were similar in both the candesartan and placebo groups. However, in some type 1 diabetic patients, hypotension could result from treatment, Dr. Sjølie said.
Dr. Sjølie would consider using candesartan in hypertensive patients with type 2 diabetes as well as those with type 1 diabetes without retinopathy who have problems with high blood sugar. “The advantage of candesartan is that it is an efficient antihypertensive drug with the potential extra benefit of improving retinopathy,” Dr. Sjølie said. She added that there are no known ocular contraindications for using candesartan for patients with diabetic retinopathy.
1 Chaturvedi, N. et al. Lancet 2008;372:1394–1402.
2 Sjølie, A. K. et al. Lancet 2008;372:1385–1393.
Dr. Sjølie has received travel grants and consultant fees from both AstraZeneca and Takeda. Both companies funded the studies.
Eye on Pediatrics
Pirenzepine Shown to Slow Myopia in Kids
Can myopia be successfully treated with an agent currently approved in Europe for the management of dyspepsia? According to researchers in the Pirenzepine Study Group (PSG), it can.
More than 80 million children worldwide are affected by myopia. Therefore, said R. Michael Siatkow ski, MD, professor of ophthalmology at the University of Oklahoma’s Dean McGee Eye Institute, “there is considerable interest in averting its progression. Researchers have studied numerous agents for the prevention or retardation of myopia. However, the only treatment prior to this study that has shown any efficacy thus far is atropine.”
Atropine, a nonselective muscarinic antagonist, produced some promising results for the treatment of myopia. However, issues of discomfort and poor compliance as well as mydriasis and cycloplegia proved problematic. As a result, researchers have turned to pirenzepine, a relatively selective M1 muscarinic receptor antagonist, which has achieved good results in animal studies and possesses a better side effect profile.
The Journal of the American Association for Pediatric Ophthalmology and Strabismus describes the results of the PSG, which found that a twice daily dosage of pirenzepine ophthalmic gel 2 percent, vs. a placebo, was an effective treatment for slowing the progression of myopia in children aged 8 to 12 years during the two-year period.1
Upon commencement of the study, spherical equivalent was –2.10 + 0.90 D among the pirenzepine group and –1.93 + 0.83 D for the placebo group. Measurements were taken at one year, and there was a mean increase in myopia of 0.26 D for the pirenzepine group, and 0.53 D for the placebo group. Participants who remained in the study for a second year had a mean increase of myopia of 0.58 D in the pirenzepine group and 0.99 D for the placebo group at the end of the study period.
As expected, accommodative dysfunction was significantly more frequent in the pirenzepine-treated group compared with placebo, but with other frequently observed events such as conjunctival papillae and follicles there was no significant difference.
But many questions about this treatment remain unanswered. Dr. Siatkowski would like to see a phase 3 study conducted to establish the most effective treatment regime: “Would better results be achieved if treatment begins at an earlier age? At what level of refractive error should treatment begin? Another spectrum of issues to contemplate is the length of time that a patient requires treatment. How long does the agent continue to maintain its effects once treatment is withdrawn? And, is there a drug rebound effect when the drug is discontinued?”
1 Siatkowski, R. M. et al. J AAPOS 2008;12(4):332–339.
Dr. Siatkowski discloses honoraria from Valley Forge Pharmaceuticals (maker of pirenzepine) from 2001 to 2005.
Daily Wear Lenses No Guarantee Against Infection
When daily disposable lenses were introduced in 1995, it was expected that rates of microbial keratitis would be reduced. The hypothesis was that the user no longer needed to clean and store contact lenses, thus eliminating what was thought to be a major culprit of microbial contamination. The same assumption held true for silicone hydrogel contact lenses, which first came on the market in 1999.
Fast-forward a decade. In a large, two-year, prospective case-control study that began in December 2003, investigators found that the risk of microbial keratitis had, in fact, not been reduced in individuals who wore daily disposables.1
The risk of developing microbial keratitis was actually higher for those who used daily disposable lenses than for those who used planned replacement daily wear lenses. However, vision loss was less likely to occur in patients with daily disposables than with reusable soft contact lenses.
In addition, the relative risk of microbial keratitis differed between brands of daily disposable lenses, was reduced for rigid lenses, and was no different for silicone hydrogel or other types of soft lenses.
“Daily disposables are intuitively the safest way to wear soft contact lenses,” noted Woodford S. Van Meter, MD, professor of ophthalmology at the University of Kentucky. “However, the study doesn’t cover the compliance issue. Patients know that if they cut corners and wear lenses longer than advised, the cost of the lenses is effectively reduced. Practitioners do not always know how well patients follow instructions. Compliance may play a role in the complications we see.”
Dr. Van Meter also noted that the differences between brands of the daily disposable lenses proved interesting. “If you think of all contact lenses as being generic equivalents for dispensing, you wouldn’t expect one lens to be significantly different from any other brand,” he said. “But the data suggest that patients in Ciba Dailies and B&L SofLens One Day had a higher rate of microbial keratitis than patients in AcuVue 1-Day lenses. This study illustrates the need for more information on compliance to explain the different risks between brands.”
Dr. Van Meter noted that a new modification of Ciba Dailies with higher water content would soon be on the market. He also wonders whether the patients in the study were prescribed daily disposables because they were at high risk for hygiene problems, which might affect the findings.
The study’s authors conclude that lens-ocular surface interactions and the differences in fit and material between daily disposable lens brands may play more of a role in the development of microbial keratitis than oxygen levels and contact lens case contamination. They stress that instructing patients on proper hygiene and wearing schedules should remain a top priority.
—Lori Baker Schena
1 Dart, J. K. G. et al. Ophthalmology 2008;115:1647–1654.
Dr. Van Meter reports no related financial interests.
New Gene Linked to AMD
British researchers have linked the SERPING1 gene to the development of age-related macular degeneration. The gene product of SERPING1 regulates the classical complement pathway, and one of the gene’s variants appears to confer protection from the disease.
In a case-control study reported in The Lancet,1 Sarah Ennis, PhD, Andrew J. Lotery, MD, and their colleagues at the University of Southampton, England, performed a low-density screen of 32 genes using 93 single nucleotide polymorphisms (SNPs) among 479 people with AMD and 479 controls. The control group comprised spouses or partners of the AMD patients or eye clinic patients being treated for an unrelated eye disorder.
Candidate genes were chosen for their suspected functional relevance, interaction with genes known to be associated with AMD or involvement in biological pathways that have been implicated in the disease. The SERPING1 gene was included because it encodes C1 inhibitor, which suppresses activation of the first component of complement (C1). Shutting down C1 disrupts the complement cascade by interfering with the activation of complement components 2 (C2) and 4 (C4).
Among the 32 genes tested, only one showed a statistically significant association with AMD—the SNP variant rs2511989, located within intron six of SERPING1. The rs2511989 A allele and AA genotype were found significantly more often in the control group than in the AMD patients, suggesting a protective effect against the disease.
Genotypic tests revealed an odds ratio of 0.63 for AMD in rs2511989 G/A heterozygotes compared with wildtype G/G homozygotes; the odds ratio for rs2511989 AA homozygotes was 0.44. About 20 to 25 percent of the population carries the rs2511989 variant.
To replicate the findings, U.S. colleagues in the University of Iowa’s department of ophthalmology and visual sciences conducted genotyping among an independent cohort of 248 AMD patients and 252 controls. The results were similar to those obtained among the U.K. cohort despite a smaller sample size. The researchers found no evidence of heterogeneity in the distribution of rs2511989 genotypes between the U.K. and U.S. samples and noted a similar excess of the rarer AA genotype among individuals in the control group.
A secondary higher density genotyping experiment conducted by the Southampton researchers identified five additional SNPs from across the SERPING1 gene region that were strongly associated with AMD.
Dr. Lotery, a professor of ophthalmology at the University of Southampton, noted that the study findings add to current evidence that dysregulation of complement metabolism due to multiple genetic defects is a major factor in the development of AMD.
“One variant of the SERPING1 gene is protective, meaning conversely that the alternate allele is associated with the disease,” Dr. Lotery said. “Our working hypothesis is that SERPING1 is not correctly inhibiting classical complement activation. As a result, patients with SERPING1 mutations experience overactivity in the classical pathway.”
He added that future research will focus on identifying the causative mutations and on understanding the effect these have on the function of SERPING1’s protein product. Ultimately, continued research in these areas should lead to earlier and more specific diagnoses and to more targeted therapies for AMD.
1 Ennis, S. et al. Lancet 2008;372(9652):1828–1834.
Financial disclosure: The University of Southampton has filed a patent application relating to the association of SERPING1 and AMD, which is currently available for licensing.
Gender Gap in Ocular Dominance
A study designed to test whether there is some correlation between ocular dominance and refractive error, spherical equivalent difference or even best-corrected vision, found none of these. But it did find something completely different. Men are more likely to be right-eye dominant than women.
While the data, based on a review of electronic medical charts of 2,453 patients whose dominance was determined using the hole-in-the card test, didn’t bear out the original hypothesis, it found that 70 percent of men, vs. 65 percent of women, were right-eye dominant, a statistically significant difference.1
The study also corroborated another study that found a tendency toward right-eye dominance.2 Sixty-seven percent of study participants favored the right eye, compared with 33 percent who favored the left.
Knowing that right-eye dominance is more common than left, and that a gender gap exists even within that pattern, won’t really affect clinical practice, said Jason E. Stahl, MD, an author of the retrospective study of patients at Durrie Vision in Overland Park, Kan., which is where he practices.
Yet knowing which eye dominates is important when treating presbyopic patients for monovision contact lenses, conductive keratoplasty or even LASIK, where one eye is adjusted for distance and the other near, he said.
“This isn’t an earth-shattering study. It’s just confirming that the dominance test is important,” said Dr. Stahl.
—Miriam Karmel ___________________________
1 Eser, I. et al. J Refract Surg 2008;24:685–689.
2 Reiss, M. R. et al. Laterality 1997;2:7–16.
EyeNet thanks Susan B. Bressler, MD, Anne E. Fung, MD, Christopher J. Rapuano, MD, and William B. Trattler, MD, for their help with this issue’s News in Review.