Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
Multicenter, ...randomized clinical trial.
A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea.
Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.
Best-corrected visual acuity and safety at 1 year.
The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.
Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.
To report expanded 2-year follow-up of a previously reported randomized trial evaluating intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid ...laser alone for treatment of diabetic macular edema (DME).
Multicenter, randomized clinical trial.
A total of 854 study eyes of 691 participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea.
Continuation of procedures previously reported for the randomized trial.
Best-corrected visual acuity and safety at the 2-year visit.
At the 2-year visit, compared with the sham + prompt laser group, the mean change in the visual acuity letter score from baseline was 3.7 letters greater in the ranibizumab + prompt laser group (95% confidence interval adjusted for multiple comparisons aCI, -0.4 to +7.7), 5.8 letters greater in the ranibizumab + deferred laser group (95% aCI, +1.9 to +9.8), and 1.5 letters worse in the triamcinolone + prompt laser group (95% aCI, -5.5 to +2.4). After the 1- to 2-year visit in the ranibizumab + prompt or deferred laser groups, the median numbers of injections were 2 and 3 (potential maximum of 13), respectively. At the 2-year visit, the percentages of eyes with central subfield thickness ≥250 μm were 59% in the sham + prompt laser group, 43% in the ranibizumab + prompt laser group, 42% in the ranibizumab + deferred laser group, and 52% in the triamcinolone + prompt laser group. No systemic events attributable to study treatment were apparent. Three eyes in 3 (0.8%) of 375 participants had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group.
The expanded 2-year results reported are similar to results published previously and reinforce the conclusions originally reported: Ranibizumab should be considered for patients with DME and characteristics similar to those of the cohort in this clinical trial, including vision impairment with DME involving the center of the macula.
Leptin targets in the mouse brain Scott, Michael M.; Lachey, Jennifer L.; Sternson, Scott M. ...
Journal of comparative neurology,
10 June 2009, Volume:
514, Issue:
5
Journal Article
Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision ...loss or worsening diabetic macular edema (DME).
To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy.
Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015.
Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME.
The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization.
Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified.
Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy.
clinicaltrials.gov Identifier: NCT01489189.
The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown.
At 89 clinical sites, we randomly assigned 660 ...adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year.
From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56).
Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).
The prevalence of persistent diabetic macular edema (DME) after months of anti-vascular endothelial growth factor therapy and its effect on visual acuity are unknown.
To assess subsequent outcomes of ...eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab.
We performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness ≥250 μm on time domain optical coherence tomography) through the 24-week visit.
Four monthly intravitreous injections of ranibizumab and then as needed per protocol.
Cumulative 3-year probabilities of chronic persistent DME (failure to achieve a central subfield thickness <250 μm and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits) determined by life-table analyses, and at least 10 letter (≥2 line) gain or loss of visual acuity among those eyes.
The probability of chronic persistent DME among eyes with persistent DME at the 24-week visit decreased from 100% at the 32-week visit to 81.1% (99% CI, 69.6%-88.6%), 55.8% (99% CI, 42.9%-66.9%), and 40.1% (99% CI, 27.4%-52.4%) at the 1-, 2-, and 3-year visits, respectively. At 3 years, visual acuity improved in eyes with and without chronic persistent DME through the follow-up period, respectively, by a mean of 7 letters and 13 letters from baseline. Among 40 eyes with chronic persistent edema through 3 years, 17 (42.5%) (99% CI, 23.1%-63.7%) gained 10 letters or more from baseline, whereas 5 (12.5%) (99% CI, 2.8%-31.5%) lost 10 letters or more from baseline.
These data suggest less than half of eyes treated for DME with intravitreous ranibizumab have persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (≥2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists.
To provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME).
Randomized phase II clinical trial.
One hundred twenty-one eyes of 121 subjects (109 eligible ...for analysis) with DME and Snellen acuity equivalent ranging from 20/32 to 20/320.
Random assignment to 1 of 5 groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22), or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n = 22).
Central subfield thickness (CST) on optical coherence tomography and best-corrected visual acuity (VA) were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks.
At baseline, median CST was 411 mum and median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction > 11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and 5 of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and 9 of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. Endophthalmitis developed in 1 eye. The following events occurred during the first 24 weeks in subjects treated with bevacizumab without attributing cause to the drug: myocardial infarction (n = 2), congestive heart failure (n = 1), elevated blood pressure (n = 3), and worsened renal function (n = 3).
These results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial. A phase III trial would be needed for that purpose.
In the hypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding and neuropeptide-Y (NPY) neurons stimulate feeding. We tested whether neurons in the ventromedial ...hypothalamic nucleus (VMH), a known satiety center, activate anorexigenic neuronal pathways in the ARC by projecting either excitatory synaptic inputs to POMC neurons and/or inhibitory inputs to NPY neurons. Using laser scanning photostimulation in brain slices from transgenic mice, we found that POMC and NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinct synaptic inputs. POMC neurons received strong excitatory input from the medial VMH (mVMH), whereas NPY neurons did not and, instead, received weak inhibitory input only from within the ARC. The strength of the excitatory input from the mVMH to POMC neurons was diminished by fasting. These data identify a new molecularly defined circuit that is dynamically regulated by nutritional state in a manner consistent with the known role of the VMH as a satiety center.
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