Ординатура / Офтальмология / Английские материалы / Current Aspects of Pathogenesis and Treatment in Diabetic Retinopathy_Kroll_2007

It should be kept in mind, however, that surgical techniques have changed considerably since conclusion of the study and that endolaser coagulation for example was not yet available in the late eighties [23, 54–58].

Diabetes Control and Complications Trial

Between 1983 and 1993 the Diabetes Control and Complications Trial (DCCT) was conducted as a clinical trial in the USA and Canada. Over 1,400 type 1 diabetics between 13 and 39 years of age who were otherwise

healthy were included [23, 48]. The study has an evidence level of 1b.

The study aimed at investigating the effect of improved blood glucose control on the onset and progression of diabetic diseases such as diabetic nephropathy, neuropathy and retinopathy. For that purpose the participants were divided into a primary prevention and a secondary intervention group. The former consisting of patients who had had diabetes for 1–5 years and did not suffer from diabetic retinoapthy, the latter consisting of patients who

risk for developing retinopathy by 76%. In patients with mild or moderate nonproliferative diabetic retinopathy at the beginning of the study, intensive management slowed the progression of the disease by 54%. Furthermore, a reduced risk was found for the development of nephropathy (50%) and for neuropathy (60%) in the intensive treatment group.

The most important side effect observed in this group was a higher risk for hypoglycemia, which is why this treatment was not recommended for younger children, older adults, patients with heart disease or advanced complications and those with a history of frequent severe hypoglycemia [23, 48].

United Kingdom Prospective Diabetes Study

The United Kingdom Prospective Diabetes Study was conducted between 1977 and 1999. Over 5000 type 2 diabetics were included. The patients without diabetic retinopathy were included into a primary prevention group, those with mild to moderate nonproliferative diabetic retinopathy were included into a secondary prevention group [23, 59, 60]. The study has an evidence level of 1b.

In this largest clinical research study both groups were then randomized into either a conventional treatment or

an intensive treatment group. The former received a diet control first, followed by sulfonylurea, insulin and metformin, the latter was treated right away with sulfonylurea and – if necessary – with insulin. Metformin was given to overweight patients.

After 10 years of follow-up a 17% reduction of diabetic retinopathy progression could be observed, as well as a 29% reduction in need for laser coagulation, a 23% reduction in vitreous hemorrhage and a 16% reduction in legal blindness. The study could also show that each of the existing therapies for treating diabetes (metformin, sulphonylureas, acarbose and insulin) were effective in reducing elevated blood glucose levels.

Furthermore, elevated blood pressure could be identified as an independent risk factor for progression of diabetic retinopathy in that trial. Beta-blockers and ACE inhibitors as blood pressure therapy were found to be equally effective in reducing the risk of diabetic complications [23, 59, 60].

Vitrectomy for Diabetic Maculopathy

Vitrectomy in cases of diabetic maculopathy was first described in 1992 by Lewis et al.. They found an improvement in patients with a taught, thickened posterior hya-

loid if vitrectomy was performed. Their study was an observational , nonrandomized clinical study consisting of 10 patients [33, 34]. In the following years several studies on vitrectomy for diabetic maculopathy were conducted. Table 5 lists all the studies that we found in MedLine. All these studies have in common that they are nonrandomized case reports with a maximum of 58 eyes in the largest study. Most studies were retrospective, a few were prospective. A minimum was controlled. Some authors performed the procedure in cases of diffuse macular edema, some in cases of cystoid macular edema and a few in both. Improvement of visual acuity was observed in 38–100% of cases. Some authors regarded a visual acuity increase of 1 line as improvement, others required a 2-line improvement. The follow-up time varied greatly amongst the studies (3–23 months). The level of evidence for these studies is therefore a maximum of 4.

More recently, peeling of the internal limiting membrane was described as adjunct to vitrectomy in cases of diabetic maculopathy. The studies describing this are listed in table 6. For these reports the same holds true as for vitrectomy without peeling of the internal limiting membrane: the authors state that the new therapy might be helpful for some patients. However, the follow-up time is short, the number of cases in each study is small, and they are mostly retrospective case reports. There are practically no larger randomized, controlled, prospective trials. The level of evidence is therefore low as well (level 4).

Intravitreal Triamcinolone Injection for Diabetic Maculopathy

In 2001, Jonas and Sofker [24] described the first case of intravitreal triamcinolone injection in a 73-year-old patient with a clinically significant diffuse diabetic macular edema, whose disease progressed despite grid laser coagulation. After the intravitreal injection of triamcinolone acetonide visual acuity improved over a 5-month follow-up period. Both Jonas and Sofker other authors applying that treatment regimen describe it as a possibly useful treatment for diabetic macular edema [27]. Table 7 lists studies using that new therapy. Most of them are interventional case reports. They are nonrandomized studies, only some had a control group. The authors still use very different dosages of the intravitreally applied triamcinolone. These studies have a level of evidence of 4 or 5 according to the grading of the Centre for EvidenceBased Medicine as well (table 1).

Discussion

EBM is practiced quite self-evidently in ophthalmodiabetology on the basis of the studies mentioned above. Treatment regimens such as laser coagulation and vitrectomy for different stages of diabetic retinopathy have been firmly established in clinical practice on a sound evidence-based foundation for many years.

EBM should be regarded as a helpful tool for any therapeutic situation which still leaves room for one’s personal clinical experience to be included. EBM is by no means restricted to large, prospective, randomized, controlled trials or meta-analyses, although these are the ‘gold’ standard for most therapeutic questions where different treatment options are compared. One can apply EBM even for special problems and very individual, difficult therapeutic questions, although at a lower level of evidence, using today’s modern means of literature research.

It is interesting to note that today’s modern therapy of diabetic retinopathy includes both high levels of evidence (1b) and very low levels (4 and 5) but hardly any studies of the 2nd or 3rd level of evidence. For established types of therapy such as laser treatment several level 1b studies exist. Newer and smaller studies regarding that established treatment regimen are no longer undertaken, and

therefore lower level of evidence studies are missing. Innovative, new therapies, however, start as a case report or a smaller case control study with a low level of evidence. They are then taken up and frequently modified by other authors. The effort of setting up larger higher level of evidence studies seems to be undertaken only if the new treatment regimen is promising or if it is regarded as highly controversial.

Despite the importance of EBM, even studies with high levels of evidence such as the Diabetic Retinopathy Vitrectomy Study need to be evaluated in the context of their time and must be questioned from time to time later on, when treatment techniques change or improve (such as development of endolaser coagulation or 25gauge minimally invasive vitrectomy), just as clinical guidelines are revised every few years and adapted to the newest scientific findings.

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Diabetes 78, 95

Diabetic macular edema 118

–retinopathy 103, 112, 132

–Retinopathy Study 95 Intravitreal injection 118 Laser photocoagulation 118

–therapy 95 Neovascularization 78 Octreotide 112

Pars plana vitrectomy 118 Proliferative diabetic retinopathy 78

–– vitreoretinopathy 78

Protein kinase C inhibitor 112 Retina 78

Ruboxistaurin mesylate 112 Somatostatin analogue 112 Surgery 103

Tractional retinal detachment 103 Treatment, evidence-based 132 Vascular endothelial growth factor 78 Vitrectomy 103, 132

Vitreous hemorrhage 103