State of the art management of diabetic macular edema

Table 1 Summary of the studies using intravitreal Bevacizumab for treatment of diabetic macular edema

Ref.	Purpose	Study design	Out comes measures	IVBdose	Interval of injection	Naive or refractory/DME	Duration of study	Number of eyes	Treatment regimen	Results
Soheilian et al[61]	IVB or IVB, IVT or MPC	Randomized clinical trial	BCVA, CMT	1.25 mg	-				(1) 1.25 mg IVB; (2) IVB/ IVT/ 1.25 mg IVB and 2 mg IVT; and (3) MPC	Group B and C had a greater reduction in CMT at 3 wk and 1 line better median VA over 12 wk there were no significant differences between group B and C. Combining MPC with IVB resulted in no apparent short term benefit
Soheilian et al[62]	IVB or IVB/ IVT or MPC	Randomized clinical trial	BCVA, CMT	1.25 mg	12 wk	Naïve	24 wk	150 eye	(1) 1.25 mg IVB; (2) IVB/ IVT 1.25 mg IVB and 2 mg IVT; and (3) MPC	The significant treatment effect on VA was demonstrated in the IVB group at all follow- up visits and in the IVB/ IVT group at 6 and 12 wk. CMT Changes were not significant among the groups in all visits
Soheilian et al[63]	the same as above	randomized clinical trial	BCVA, CMT	1.25 mg	12 wk	Naïve	2 yr	150 eyes	The same as above	The significant superiority of VA improvement in the IVB group, which had been noted at month 6, did not sustain thereafter up to 24 mo, and the difference among the groups was not significant at all visits. The reduction of CMT was more in the IVB group in relation to the other two treatment groups however, the difference among the groups was not significant at any of the follow-up visits
DRCR.Net[64]	IVB for DME	Randomized phase 2 clinical trial	CMT, BCVA	1.25 mg 2.5 mg	6 wk	Naive	24 wk	121	(1) Foal MPC12 or (2) 1.25 mg IVB at base line and 6 wk; (3) 2.5 mg IVB6 at baseline and 6 wk or (4) 1.25 mg at baseline; and (5) 1.25 mg IVB at base line and 6 wk + MPC at 3 wk	The significant treatment effect on VA was demonstrated at both 6 and 12 wk in the IVB group and only at 6 wk in the IVB/IVT group. Significant CMT reduction was observed in eyes in the IVB and IVB/ IVT groups only up to 6 wk, however, CMT changes were not significant in the groups
Marey et al[65]	IVB or IVB/ IVT for DME	Randomized clinical trial	VA and CMT	1.23 mg		Naïve	12 wk	90	(1) IVB; (2) IVB and IVT (4 mg); and (3) IVT	There was significant improvement in the VA in the three study groups at week 6 and 12. Comparing the visual acuity results at 6 wk between the 3 study groups there was no significant difference and also between each pair of the three study groups; however at week 12, there was high significant difference (P = 0.004) and between each pair there was high significant difference between IVT and IVB/ IVT groups (P = 0.001), significant difference between groups IVT and IVB and no significant difference between group IVB/ IVT and IVB. Comparing the CMT showed the same results
Lim et al[66]	IVB or IVB/ IVT or IVT	Randomized 3arm clinical trial	BCVA, CMT	1.25 mg	6 wk	Naïve	12 mo	111 eyes	IVB group, two IVB injections with 6 wk intervals; IVB / IVT (2 mg IVT + 1.25 mg IVB); 2 mg IVT	The IVB/ IVT group and IVT group showed better visual acuity and reduced CMT at 6 wk and 3 mo. However, no significant difference in VA and CMT was observed between 3 groups. No significant differences in VA or CMT were observed between the IVB/ IVT and IVT group during the follow- up
Ahmadieh et al[67]	IVB or IVB/T for refractory DME	Randomized clinical trial (Placebo- Controlled)	CMT BCVA	1.25 mg	6 wk	Refractory	24 wk	115 eyes	(1) three injection of 1.25 mg IVB at 6 wk intervals; (2) IVT (2 mg) followed by two injections of IVB at 6 wk intervals; and (3) sham injection	CMT was reduced significantly in both IVB and IVB/ IVT groups. Significant improvement of BCVA was seen in both IVB and IVB/ IVT groups. No significant differences were detected in the changes of CMT and BCVA between the IVB and IVB/IVT groups
BOLT study[68]	IVB or MPC for DME	Randomized clinical trial	BCVA	1.25 mg	6 wk	Refractory /DME	12 mo	80 eyes	IVB MPC	The mean ETDRS BCVA at 12 mo was 61.3 ± 10.4 in the IVB group and 50.0 ± 16.6 in the MPC group. The IVB group gained a median of 8 ETDRS letters, whereas the MPC group lost a median of 0.5 ETDR letters. At 12 mo, CMT decreased from 507 ± 145 μm at baseline to 378 ± 134 μm (P < 0.001) in the IVB group, whereas it decreased to a lesser extent in the MPC group, from 481 ± 121 μm to 413 ±135 μm (P = 0.02)

IVB: Intravitreal bevacizumab; IVP: Intravitreal pegaptanib; IVR: Intravitreal ranibizumab; IVT: Intravitreal triamcinolone; IVTL: Intravitreal triamcinolone plus laser; IVVTE: Intravitreal VEGF Trap Eye; DME: Diabetic macular edema; BCVA: Best corrected visual acuity; CMT: Central macular thickness.

Table 2 Summary of the studies using intravitreal Ranibizumab for treatment of diabetic macular edema

Name ofstudy	Purpose	Study design	Outcomes measures	IVR dose	Interval of injection	Naive or refractory /DME	Duration of study	Number of eyes	Treatment regimen	Results
READ-2 study[73]	IVR for DME	3-arm RCT	BCVA and CMT	0.5 mg	1 and 2 mo	Naïve or refractory	2 yr	126	Group 1 (IVR, n = 42 eyes) injections of 0.5 mg ranibizumab at baseline, 1, 3 and 5 mo Group 2 (L, n = 42 eyes) focal/grid laser at baseline and 3 mo if CMT ≥ 250 μm Group 3 (IVRL, n = 42 eyes) IV injections of 0.5 mg ranibizumab at baseline and 3 mo, followed by focal/grid laser treatment 1 wk later	BCVA changes (letters) P value IVR +7.24 0.0003 vs L L -0.43 IVRL +3.80 CMT changes (μm) IVR -106.3 All < 0.01 vs baseline L -82.8 IVRL -117.2
RESTORE study[74]	IVR for DME	3-arm RCT	BCVA and CMT	0.5 mg	1 mo	Naïve or refractory	1 yr	345	Group 1 (IVR, n = 116 eyes) IV ranibizumab plus sham laser Group 2 (IVRL, n = 118 eyes) 0.5 mg IV ranibizumab plus active laser Group 3 (L, n = 111 eyes) laser treatment plus sham injections	BCVA changes (letters) P value IVR +6.1 SD6.43 < 0.0001 IVRL +5.9 SD7.92 < 0.0001 L +0.8 SD8.56 CMT changes (μm) P value IVR -118.7 < 0.0002 IVRL -128.3 < 0.0001 L -61.3
REVEAL study[75]	IVR for DME	3-arm RCT	BCVA and CMT	0.5 mg	1 mo	NR	1 yr	396	Group 1 (IVR 0.5 mg + sham laser, n = 133) day 1, month 1, 2 and pro-renata thereafter based on BCVA Group 2 (IVR 0.5 mg + active laser, n = 132) day 1, month 1, 2 and pro-renata thereafter based on BCVA Group 3 (sham injection + active laser, n = 131)	BCVA (letters) and CRT(μm) changes: P value IVR + sham laser +6.6; -148.0 < 0.0001 IVR +laser +6.4; −163.8 < 0.0001 Laser + sham +1.8; -57.1
RESOLVE study[76]	IVR for DME	3-arm RCT	BCVA and CMT	0.3 and 0.5 mg	1 mo	Naïve and refractory	1 yr	151	Group 1 (IVR 0.3, n = 51 eyes) 0.3 mg (0.05 mL) IV ranibizumab, 3 monthly injections Group 2 (IVR 0.5, n = 51 eyes) 0.5 mg IV (0.05 mL) ranibizumab, 3 monthly injections Group 3 (C, n = 49 eyes) sham	BCVA changes P value IVR 0.3 +11.8 SD6.6 < 0.0001 vs C IVR0.5 +8.8 SD11.0 < 0.0001 vs C C -1.4 SD14.2 CMT (μm) P value IVR0.3 -200.7 SD122.2 < 0.0001 vs C IVR0.5 -187.6 SD147.8 < 0.0001 vs C C -48.4 SD153.4
RISE study[77]	IVR for DME	3-arm RCT	BCVA and CMT	0.3 and 0.5 mg	1 mo	Naïve or refractory	2 yr	377	Group 1 (IVR 0.3 mg, n = 125 eyes) Group 2 (IVR 0.5 mg, n = 125 eyes) Group 3 (C, n = 127 eyes): sham injection	BCVA changes (letters): P value IVR0.3 +12.5 < 0.0001 IVR0.5 +11.9 < 0.0001 C +2.6 CFT (μm): IVR0.3 -250.6 < 0.0001 IVR0.5 -253.1 < 0.0001 C -133.4
RIDE study[77]	IVR for DME	3-arm RCT	BCVA and CMT	0.3 and 0.5 mg	1 mo	Naïve or refractory	2 yr	382	Group 1 (IVR 0.3 mg, n = 125 eyes) Group 2 (IVR 0.5 mg, n = 127 eyes) Group 3 (C, n = 130 eyes): sham injection	BCVA (letters) and CMT (μm): P value IVR0.3 +10.9, -259.8 < 0.0001 IVR0.5 +12.0, -270.7 < 0.0001 C +2.3, -125.8

DME: Diabetic macular edema; BCVA: Best corrected visual acuity; CMT: Central macular thickness. IVR: Intravitreal ranibizumab.

Table 3 Summary of the studies using intravitreal Pegaptanib for treatment of diabetic macular edema

Ref.	Purpose	Study design	Out comes measures	IVP dose	Interval of injection	Naive or refractory /DME	Duration of study	Number of eyes	Treatment regimen	Results
Cunningham et al[81]	IVP for DME	RCT	BCVA and CMT	0.3, 1 and 3 mg	1 mo	Naive	36 wk	172	Group 1 (IVP0.3, n = 44 eyes) 0.3 mg IV pegaptanib (90 μL) [median 5 injections (range 1-6)] Group 2 (IVP1, n = 44 eyes) mg IV pegaptanib (90 μL) [median 6 injections (range 3–6))] Group 3 (IVP3, n = 42 eyes) 3 mg IV pegaptanib (90 μL) (median 6 injections (range 1-6) Group 4 (C, n = 42 eyes): sham injection	BCVA changes (letters) P value IVP0.3 +4.7 0.04 IVP1 +4.7 0.05 IVP3 +1.1 NS C -0.4 CMT changes (μm,) IVP0.3 -68.0 0.02 IVP1 -22.7 NS IVP3 -5.3 NS C +3.7
Sultan et al[83]	IVP for DME	RCT	BCVA and CMT	0.3 mg	6 wk	Naive	2 yr	260	Group 1 (IVP, n = 133 eyes): 0.3 mg IV pegaptanib Group 2 (C, n = 127 eyes) sham injection	BCVA changes (letters) P value IVP +5.2 < 0.05 C +1.2 CMT (OCT): Decrease in CMT IVP ≥ 25%: 31.7% NS ≥ 50%: 14.6% NS C ≥ 25%: 23.7% ≥ 50%: 11.9%

DME: Diabetic macular edema; BCVA: Best corrected visual acuity; CMT: Central macular thickness; IVP: Intravitreal pegaptanib.

Table 4 Summary of the study using intravitreal Aflibercept for treatment of diabetic macular edema

Name of study	Purpose	Study design	Out comes measures	IVA Dose	Interval of injection	Naive or refractory /DME	Duration of study	Number of eyes	Treatment regimen	Results
DA VINCI[84,85]	IVVTE for DME	RCT	IVA f or DME	0.5 and 2 mg	1 and 2 mo	Naïve or refractory	1 yr	221	Group 1 (IVVTE1, n = 44 eyes): IVVTE, 0.5 mg every 4 wk Group 2 (IVVTE2, n = 44 eyes): IVVTE, 2 mg every 4 wk Group 3 (IVVTE3, n = 42 eyes): IVVTE, 2 mg for 3 initial mo then every 8 wk Group 4 (IVVTE4, n = 45 eyes): IVVTE, 2 mg for 3 initial months then as needed Group 5 (L, n = 44 eyes): laser photocoagulation Laser modified ETDRS protocol	BCVA changes (letters) P value IVVTE1 +8.6 0.005 IVVTE2 +11.4 < 0.0001 IVVTE3 +8.5 0.008 IVVTE4 +10.3 0.0004 L +2.5 CMT(μm) IVVTE1 -144.6 0.0002 IVVTE2 -194.5 < 0.0001 IVVTE3 -127.3 0.007 IVVTE4 -153.3 < 0.0001 L -67.9

DME: Diabetic macular edema; IVTL: Intravitreal triamcinolone plus laser; IVVTE: Intravitreal VEGF Trap Eye; IVA: Intravitral aflibercept.

Table 5 Summary of the studies using intravitreal steroid for treatment of diabetic macular edema

Agent	Number of patients	Total dose (daily release	Duration	Main outcomes
IVTA[86]	693	4 mg TA (Trivaris and triesence) (unknown)	Approximately 3 mo	Less favorable results vs photocoagulation at 24 and 36 mo
Fluocinolone acetonide implant (ILUVIEN)[90]	956	180 μg (0.5 μg or 0.2 μg/d)	Up to 3 yr	Generally favorable outcomes at 36 mo
Fluocinolone acetonide implant (retisert)[91]	197	500 μg FA (0.59 μg/d)	2.5 yr	Effective DME therapy at 36 mo, however high risks of cataract and glaucoma
Dexamethasone drug delivery system (ozurdex)[92]	171	750 μg dexamethasone (estimated approximately 6.25 μg/d)	Approximately 4 mo	Generally favorable outcomes at 90 d

DME: Diabetic macular edema; IV: Intravitreal; IVTA: Intravitreal triamcinolone; TA: Triamcinolone; FA: Fluocinolone acetonide.