Reviews/Commentaries/ADA Statements PERSPECTIVES ON THE NEWS

Diabetic Retinopathy and Diabetic Neuropathy

ZACHARY T. BLOOMGARDEN, MD in the time to progression and a 40% re- duction in the likelihood of developing PDR but no difference in macular . Perspectives on the News commentaries are directly in the to reduce VEGF Serum IGF-1 levels were suppressed by ϳ now part of a new, free monthly CME activ- production and to decrease retinal neo- 50%, although they appeared to in- ity. The Mount Sinai School of Medicine, vascularization, with three of the five so- crease during the period of observation. New York, New York, is designating this ac- matostatin receptor subtypes having been In Study 802, however, although IGF-1 tivity for 2.0 AMA PRA Category 1 credits. If identified in the retina. levels were suppressed, there was no sig- you wish to participate, review this article Octreotide is an eight–amino acid nificant delay in time to progression to and visit www..procampus.net to synthetic peptide acting at somatostatin PDR at either dose and no difference in complete a posttest and receive a certificate. receptors. In a 15-month study of the macular edema, with the 30-mg dose as- The Mount Sinai School of Medicine is ac- effect of administration of octreotide to sociated with improvement in visual acu- credited by the Accreditation Council for diabetic individuals with severe nonpro- ity at a level of significance of 0.03; Continuing Medical Education (ACCME) to liferative (NPDR) or early proliferative although given the multiple comparisons, provide continuing medical education for (PDR) , 11 patients their statistical criterion was P Ͻ 0.025. physicians. receiving treatment were compared with There was no difference in albuminuria in 12 control subjects, with 5 vs. 40% re- either study. Adverse effects of treatment his is the sixth in a series of articles quiring panretinal photocoagulation over included 70 vs. 33% incidence of diar- on presentations at the American 15 months (5). In a similar study, among rhea, 44 vs. 19% of cholelithiasis, 43 vs. T Diabetes Association’s 66th Scien- nine patients with persistent high-risk 38% of , and 20 vs. 12% of tific Sessions, Washington, DC, 9–13 PDR after panretinal photocoagulation abdominal . A1C levels tended to be June 2006, reviewing aspects of diabetic treated with 100 mcg octreotide three stable and were not influenced by treat- retinopathy and neuropathy and lower times daily for 36 months, there was one ment with octreotide. At this point, then, extremity vascular . small vitreous hemorrhage, while nine there is a suggestion of benefit in some Maria Grant (Gainesville, FL) dis- control subjects experienced five dense individuals with diabetic retinopathy, but cussed the treatment of diabetic retinop- hemorrhages requiring surgery, with evi- octreotide cannot be recommended for athy with -like growth factor dence that octreotide led to preserved vi- general use in the condition. (IGF)-1 antagonists, reviewing a number sual acuity (6). Paul Dodson (Birmingham, U.K.) dis- of lines of evidence. There is evidence of The long-acting acetate of octreotide cussed the complex relationship between hypersecretion of growth hormone in di- is an injectable depot formulation main- dyslipidemia and diabetic retinopathy abetes. Furthermore, diabetic retinopathy taining circulating levels for 1 month, and the question of whether lipid- has been seen following administration of used clinically in treatment of acromegaly lowering treatment improves diabetic ret- growth hormone to individuals without at typical doses of 10–20 mg monthly. inopathy. Combined is diabetes (1); there is evidence of reduc- There is case-report evidence of a clinical associated with peripheral ischemia, cot- tion in diabetic retinopathy in growth benefit in diabetic retinopathy (7). Grant ton wool spots, and exudates. Familial hormone–deficient individuals (2), and reviewed two phase III randomized con- hypercholesterolemia is not directly asso- pituitary ablation has been shown to have trolled clinical trials, in individuals with ciated with retinopathy, although it is a a benefit in reducing diabetic retinopathy moderate and severe NPDR not requiring risk factor for retinal vein and arterial oc- progression (3). A number of studies have laser therapy treated with 30 mg oct- clusion, with individuals having high de- addressed the potential benefit of soma- reotide monthly: Study 804 of 313 pa- grees of carotid stenosis sometimes tostatin and its analogs in the treatment of tients carried out in the U.S., Brazil, and developing an ocular ischemic syndrome. diabetic retinopathy (4). IGF-1 causes a Canada comparing 30 mg versus The combination of both hyperlipidemia phosphatidylinositol 3-kinase–mediated and Study 802 of 585 patients carried out and diabetes is associated with retinal ab- increase in vascular endothelial growth in Europe comparing 30 mg, 20 mg, and normality. In the Atherosclerosis Risk In factor (VEGF) expression by retinal pig- placebo. The majority of enrolled individ- Community (ARIC) Study, carotid inti- ment epithelial cells leading to effects on uals had , most had mi- ma-media thickness was associated with retinal endothelial cells. Somatostatin re- croalbuminuria, and the mean A1C was diabetic retinopathy. There is a significant duces circulating IGF-1, as well as acting 8–8.4%. In Study 804, there was a delay increase in LDL cholesterol with worsen- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ing grades of retinopathy (8). As choles- Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with terol quartile increases, there is increased the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. risk of maculopathy and proliferative ret- Abbreviations: AGE, advanced glycation end product; ARIC, Atherosclerosis Risk In Community; CVD, inopathy. In the Diabetes Control and cardiovascular disease; ICAM, intracellular adhesion molecule; IGF, insulin-like growth factor; NF␬B, nu- Complications Trial, the highest quintile clear factor-␬B; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; PKC, kinase C; STZ, streptozotocin; VEGF, vascular endothelial growth factor. of LDL cholesterol showed a doubling in DOI: 10.2337/dc07-zb03 likelihood of clinically significant macular © 2007 by the American Diabetes Association. edema and hard exudates (9). LDL, par-

760 DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 Bloomgarden ticularly if glycated or oxidized, may be cular permeability. Fundoscopic exam is, (abstract numbers refer to the American associated with decreased cell growth, however, imprecise (17), and easily de- Diabetes Association Scientific Sessions, potentially mediating some aspects of di- tectable but more severe changes such as Diabetes 55 [Suppl. 1], 2006). Further in- abetic retinopathy. An association has hemorrhages are infrequent in individu- formation from this survey shows that, been reported between statin use and als with , leading to the use among individuals with diabetes aged lower risk of development of vitreous of systematic retinal vascular grading per- Ն65 years, 16 and 9% had visual acuity hemorrhage (10), and several small stud- formed by ophthalmologists, using sub- Ͻ20/40 with and without correction ies have suggested that pravastatin (11) jective assessment of retinal photographs, (25). Coleman et al. (abstract 229) ana- and atorvastatin (12) improve some as- or, more recently, the development of lyzed the risk of developing diabetic reti- pects of diabetic retinopathy. computer techniques to allow rapid and nopathy among 1,949 individuals Statins may lower intraocular pres- objective assessment of retinal vascular enrolled in the UK Prospective Diabetes sure, and some studies have shown that characteristics, such as the degree of arte- Study who did not have diabetic retinop- fibrates decrease retinal exudates. Results riolar branching, bifurcation angles, and athy at baseline, finding association with of two large clinical trials are of interest. In venous tortuosity. Large datasets from A1C, blood pressure, and urine albumin CARDS (Collaborative Atorvastatin Dia- population-based studies including the Ͼ300 mg/l, while smoking and increased betes Study), 2,838 individuals with dia- ARIC Study, the Beaver Dam Eye Study, age were associated with lower risk. Ru- betes with 30% diabetic retinopathy the Blue Mountains Eye Study, the Wis- bino et al. (abstract 823) reviewed medi- prevalence at baseline were randomized consin Epidemiological Study of diabetic cal records from clinics in France, Italy, to atorvastatin versus placebo, with a retinopathy, the Multi-Ethnic Study of Spain, and the U.K. (mean of 41 clinics/ nonsignificant trend to decrease in re- Atherosclerosis, and the Rotterdam Study country), finding respective prevalences quirement for laser treatment in 17.9 vs. have shown up to a 14% prevalence of of diagnosed diabetic retinopathy of 11, 20.5% at a mean 3.9-year follow-up (13). retinal abnormality, having strong associ- 18, 10, and 20% in general practices. Of In the FIELD (Fenofibrate Intervention ation with blood pressure (18), with a lin- 752 patients with diabetic retinopathy, and Event Lowering in Diabetes) Study, ear relationship between blood pressure ϳ40% had mild, 16–28% moderate, and 9,795 participants aged 50–75 years with and the degree of retinal arteriolar nar- 2–4% severe NPDR, and 20–30% had type 2 diabetes not taking statin therapy rowing (19). There is also an association PDR. Skrivarhaug et al. (abstract 967) were randomized to placebo versus feno- of smaller arteriolar-venous ratio with in- studied 294 individuals developing type fibrate. At baseline, 8% had diabetic reti- creased likelihood of diabetes (20) and of 1 diabetes before age 15 in Norway be- nopathy; at 5 years of follow-up, 253 retinal vessel caliber to the likelihood of tween 1973–1982, with retinal imaging control subjects (5.2%) versus 178 progression of diabetic retinopathy (21). in 1989–1990 showing no diabetic reti- (3.6%) individuals allocated fenofibrate More specific abnormalities, such as cot- nopathy in 194 individuals, 163 of whom needed one or more laser treatments for ton wool spots, were associated with a had diabetic retinopathy in 2002–2003. retinopathy, a highly significant reduc- ninefold greater increase in stroke in the PDR was found in the second set of pho- tion, concordant with the reduction in al- ARIC Study (22). Further analysis of this tographs in 31 individuals, with signifi- buminuria reported in the study (14). study showed that risk of failure was cant predictors the presence of Thus, there is intriguing evidence of a markedly increased in individuals with retinopathy at the initial exam, A1C benefit of lipid-lowering therapies on di- retinal abnormality, with the presence of Ͼ9.9%, and triglyceride Ͼ141 mg/dl. abetic retinopathy, suggesting an addi- hypertension not adding further risk in The authors pointed out the importance tional rationale to the well-established multivariate analysis of individuals with of modifiable risk factors. Sun et al. (ab- benefit in cardiovascular disease (CVD) diabetic retinopathy (23). Finally, in the stract 825) studied diabetic retinopathy prevention. Beaver Dam Study, retinal microvascular among 98 individuals who received the Gabriella Tikellis (Melbourne, Aus- abnormality was associated with coronary Joslin Clinic 50-year Medal for living Ն50 tralia) discussed the concept of the eye as mortality (24). Tikellis concluded that years with , finding that a risk marker for CVD. The association of there is strong and consistent correlation 7% had no diabetic retinopathy, 39% had retinal microvascular abnormality was of blood pressure with a number of retinal mild, 8% moderate, and 1% severe first reported more than a century ago findings and some evidence of association NPDR, while 42% had PDR. In addition, (15), with studies in the 1930s showing with CVD; thus, the retinal exam, partic- 63% had visual acuity 20/20 or better. that the severity of retinal microvascular ularly when making use of detailed as- Neither diabetic retinopathy severity nor abnormality was predictive of 3-year sessment of retinal photographs, may add visual acuity correlated with duration, age mortality in individuals with hyperten- independent information about risk and of onset, A1C, lipids, BMI, C-peptide, sion (16). Tikellis described the retinal prognosis. GAD antibodies, or HLA DQB1, DQA1, circulation as a “window to the systemic A number of research presentations at and DRB1 genotypes, suggesting that a circulation,” with retinal vessels sharing the American Diabetes Association Scien- large minority of individuals with type 1 many characteristics with those of other tific Sessions addressed aspects of diabetic diabetes are protected against complica- organs. Focal or localized retinal vascular retinopathy. Zhang et al. (abstract 992) tions by factors yet to be characterized. findings may include focal arteriolar nar- analyzed the NHANES (National Health Several studies addressed potential rowing, arteriovenous nicking, arteriolar and Nutrition Examination Survey) mechanisms of diabetic retinopathy. Al- wall thickening, and diabetic retinopa- 1999Ϫ2002, finding visual acuity better Shabrawey et al. (abstract 15-LB) studied thy–like lesions, including hemorrhages, than 20/200 but Ͻ20/40 among 5% of streptozotocin (STZ)-induced diabetic microaneurisms, and cotton-wool spots, individuals with and 2.3% of those with- mice, finding increased albumin extrava- while macular edema may be regarded as out diabetes, while 1.3 and 0.6%, respec- sation from retinal vessels, suggesting ab- a sign of generalized abnormality of vas- tively, were blind (visual acuity Յ20/200) normality of the blood-retinal barrier and

DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 761 Perspectives on the News increased retinal vascular leukocyte adhe- sessed by retinal fluorescein angiography, 5% gaining Ն15 letters on the chart. Of sion and intracellular adhesion molecule with decreased lens and vitreous levels of those with clinically significant macular (ICAM)-1 expression, in conjunction the advanced glycation end product edema Ͼ100 ␮m from the center of the with increased retinal reactive oxygen (AGE) pentosidine and decreased retinal macula, 67 vs. 50% progressed to the species production determined in sec- VEGF mRNA expression, all in a dose- high-risk state of having this degree of tions using dichlorofluroscein imaging. dependent manner, with the authors macular edema Յ100 ␮m from the center Diabetic mice either with deletion of the speculating the AGE-reducing effect to be of the macula. The authors concluded NAD(P)H oxidase subunit gp91 phox primary. Lee et al. (abstract 504) reported that ruboxistaurin showed evidence of gene or treated with the NAD(P)H oxi- that magnolol, a polyphenolic compound protection against macula edema and dase inhibitor; apocynin, however, had derived from the bark of Houpu magnolia against loss of visual acuity in patients normal reactive oxygen species forma- used in Chinese traditional medicine, de- with moderately severe to very severe tion, ICAM-1 expression, leukostasis, and creases AGE formation and lens aldose re- NPDR. Tuttle et al. (abstract 436) re- blood-retinal barrier. The retrovirus- ductase activity, with reduced lens ported renal safety data in the two associated DNA sequence (ras) originally opacity and reduced sciatic sorbitol ruboxistaurin trials, showing neither pro- isolated from Harvey murine sarcoma vi- in STZ-induced diabetic rats. Gubitosi- tective nor on the glomeru- ruses (H-ras) encodes phosphohydrolase Klug and Kern (abstract 225) studied lar filtration rate or the likelihood of G- that hydrolyze GTP to GDP, STZ-induced diabetes in animals with progression to glomerular filtration rate acting to regulate aspects of cellular and without expression of 5-lipoxygen- Ͻ30 ml/min per 1.73 m2. Albuminuria growth and differentiation. Kowluru et al. ase, an enzyme essential to synthesis of was not discussed in this presentation, (abstract 227) reported that H-ras expres- eicosanoids, finding decreased numbers but the author has previously reported re- sion increases after exposure of bovine of acellular retinal and reduced duction in albuminuria with ruboxistaurin retinal endothelial cells to high retinal adhesion of leukocytes, suggesting administration to individuals with estab- and that overexpression of H-ras in- a potential proinflammatory target for lished nephropathy (28). Casellini et al. creases the effect of glucose exposure on prevention of diabetic retinopathy. Small (abstract 791) reported a 39% improve- nitric oxide, nuclear factor-␬B(NF␬B), interfering antisense RNA sequences ment in the neuropathy measure in 20 and apoptosis, while retinal endothelial serve as guides for the cleavage of homol- individuals receiving ruboxistaurin and a cells overexpressing an inactive ras mu- ogous mRNA in the RNA-induced silenc- 2% improvement in 20 receiving placebo, tant have reduced effect of high glucose ing complex. Chen et al. (abstract 818) with no significant differences in electro- on these processes. Mu et al. (abstract found that diabetes increased retinal lev- physiology; skin nerve fiber density; 822) found that PDR was associated with els of the transcriptional coactivator quantitative sensory testing of vibration, increased vitreous and serum levels of an- p300, as well as of fibronectin and NF␬B, cold, or warm sensation thresholds; car- giopoietin-2, which appears to down- and found that intravitreal small interfer- diac autonomic reflex testing; skin micro- regulate new branching and ing antisense RNA targeted toward p300 vascular blood flow; or neuropathy sprouting, antagonizing the effect of an- reduced p300, fibronectin, and NF␬B, measure. Endothelium-dependent skin giopoietin-1 at the TIE-2 endothelial cell suggesting a potential treatment ap- blood flow doubled after local warming in receptor. Angiopoeitin-2 levels may cor- proach. Hu et al. (abstract 820) found in- individuals receiving ruboxistaurin but relate with the degree of angiogenic activ- creased retinal levels of the adhesion not those receiving placebo. Brooks et al. ity in PDR, suggesting an additional molecules vascular cell adhesion mole- (abstract 790), however, failed to find ef- pathway to that of VEGF, which may play cule-1 and ICAM-1 in STZ-diabetic rats fects of ruboxistaurin treatment on the neu- a role in diabetic retinopathy. and found that the phosphordiesterase III ropathy measure or in skin blood flow in Several studies in animal models sug- inhibitor cilostazol reduced both mRNA nine treated individuals compared with gest potential new therapies for diabetic expression and protein levels of ICAM-1, nine receiving placebo. Tesfaye et al. (ab- retinopathy. Chen et al. (abstract 16-LB) vascular cell adhesion molecule-1, as well stract 813) reported no overall effects of studied the effect of erythropoietin on ox- as decreasing PPAR␣ and PPAR␥, sug- ruboxistaurin on neuropathy in data from ygen-induced retinal vascular degenera- gesting another potential treatment. 519 individuals with symptomatic neurop- tion in a neonatal mouse model, showing There has been interest in the use of athy pooled from two 1-year randomized that hyperoxia suppressed retinal eryth- inhibitors of protein kinase C (PKC)-␤ in controlled trials, with improvement of at ropoietin mRNA more than fivefold, with the treatment of diabetic retinopathy. Ai- least 50% from baseline in 43%, suggest- a rebound Ͼ10-fold increase after subse- ello et al. (abstract 230) analyzed the com- ing that a marked placebo effect exists in quent room air exposure, with systemic bined data from two 3-year randomized diabetic neuropathy. Interestingly, those erythropoietin administration before and controlled trials (26,27) comparing 401 individuals using insulin at baseline and during hyperoxia reducing retinal vaso- individuals receiving placebo and 412 those with non-Caucasian ethnicity had obliteration and subsequent neovascular- treated with the PKC-␤ inhibitor greater likelihood of clinically significant ization, although administration of ruboxistaurin, 32 mg daily, in individuals symptom reduction, while there was a erythropoietin after oxygen exposure with moderate to very severe NPDR. trend to decreased symptom reduction failed to have a protective effect. Mogami Moderate visual loss, defined as loss of among those receiving statins. King et al. et al. (abstract 226) studied retinal abnor- Ն15 letters (three lines) on the Early (abstract 506) compared overall clinical mality in the spontaneously diabetic Torii Treatment Diabetic Retinopathy Study vi- safety among 1,396 diabetic individuals (SDT) rat model of type 2 diabetes, find- sual acuity chart, sustained for the last 6 treated with ruboxistaurin and 1,408 re- ing that the angiotensin II receptor months on study, occurred in 10% of ceiving placebo in 11 clinical trials, find- blocker candesartan reduced cataract for- those receiving placebo and in 6% of ing no evidence of adverse events and mation and vascular permeability as- those receiving ruboxistaurin, with 2 vs. excellent tolerability, without change in

762 DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 Bloomgarden blood pressure or glycemic control. Thus, with two large studies having been carried stand the pathogenesis of pain in neurop- there is a suggestion of clinical benefit for out with . The first compared athy and distinguish peripheral from diabetic retinopathy with ruboxistaurin; placebo with 20, 60, and 120 mg daily central pain, with a potentially important although the U.S. Food and Drug Admin- doses in 457 individuals with painful di- contributory factor being spinal cord ab- istration has not felt these trials offered abetic neuropathy, showing significant normality (43), which his group has sufficient evidence to allow its approval pain relief with the higher doses and evi- found to occur early in the development (29). dence of benefit at the lowest dose as well of diabetic neuropathy (44). Magnetic beginning at 1 week and maintained over resonance imagining sprectroscopy Diabetic neuropathy the 12 weeks of study (33). The second shows abnormality of the thalamus, Solomon Tesfaye (Sheffield, U.K.) dis- study compared 120 mg once daily with which acts as a gateway for pain, to occur cussed pharmacologic approaches to the 60 mg twice daily for 6 months in 449 in individuals with painful neuropathy. treatment of individuals with painful dia- patients, showing maintenance of pain re- There is also evidence of greater degrees betic neuropathy (30). Diabetic periperal lief through 28 weeks (34). A number of of neuronal function impairment in pain- neuropathy starts in the toes and gradu- side effects were reported, including nau- less than in painful neuropathy, with ally affects more proximal areas, causing sea, somnolence, dizziness, constipation, nerve blood flow impaired to a greater ex- pain in ϳ30% of patients. Neuropathy is dry mouth, and reduced appetite, with 36 tent and oxygen saturation lower in indi- associated with cardiovascular risk factors and 37% of the respective groups not viduals with painless than in those with and, independently, with the presence of completing the second study and 20 and painful neuropathy (45). Acute painful CVD; therefore, the presence of neuropa- 27% discontinuing because of side ef- neuropathy occurring in the setting of thy is a marker of individuals at increased fects. was studied in 75, 150, normalization of glycemia may be associ- risk for mortality. In his study of 1,172 and 225 mg extended release daily doses, ated with proliferative retinopathy and individuals with type 1 diabetes followed the latter two leading to significant im- with new vessel formation on the surface for 7 years, baseline A1C, the change in provement in pain score, although side of the nerve, further suggesting important A1C, and duration of diabetes were risk effects included somnolence, , and functional differences between painful factors. After adjustment for these factors, myalgia, and 7 of the 244 treated patients and painless neuropathy. Tesfaye retuned higher LDL cholesterol and triglycerides, developed significant electrocardio- to the theme of pathogenic treatment for higher BMI, hypertension, and smoking graphic abnormality (35). A study com- neuropathy, suggesting that studies with predicted development of neuropathy, paring venlafaxine with the tricyclic the PKC-␤ inhibitor ruboxistaurin and with baseline CVD associated with dou- showed similar improvement with aldose reductase inhibitors suggest bled risk of neuropathy (31). in (36). that it may become possible to develop The clinical syndrome is character- Several other agents are being stud- treatment approaches that successfully ized by burning discomfort with noctur- ied. reduces neural calcium in- address the metabolic dysfunction of dia- nal exacerbation, as well as by autonomic flux, decreasing neurotransmitter release, betes. manifestations and insensitivity leading and has been studied in four randomized to foot ulceration and . Inter- controlled trials including 146–724 indi- vention can either be symptomatic or viduals with painful diabetic neuropathy, References pathogenic to alter the course of neurop- showing pain relief within 1 week and 1. Koller EA, Green L, Gertner JM, Bost M, Malozowski SN: Retinal changes mimick- athy, the latter exemplified by efforts to persisting through the 6- to 12-week ing diabetic retinopathy in two nondia- achieve euglycemia. A number of agents studies (37–40). A number of prominent betic, growth hormone-treated patients. have been used for analgesia. The tricyclic side effects were observed, with dose- J Clin Endocrinol Metab 83:2380–2383, are effective, although related somnolence, ataxia, and confu- 1998 Tesfaye remarked that he finds these sion, as well as peripheral edema and 2. Merimee TJ: A follow-up study of vascular agents to be associated with high levels of constipation reported. leads disease in growth-hormone-deficient side effects, with other relatively estab- to significant benefits at 8 and 12 weeks at dwarfs with diabetes. N Engl J Med 298: lished approaches including anticonvul- 400-mg daily dosages but, again, with 1217–1222, 1978 sants, particularly carbemazepine and high frequency of side effects, including 3. Sharp PS, Fallon TJ, Brazier OJ, Sandler , topical , oral mexil- , loss of appetite (which may be L, Joplin GF, Kohner EM: Long-term follow-up of patients who underwent etine, and topical isosorbide and capsa- beneficial, as the agent is associated with yttrium-90 pituitary implantation for icin. Tesfaye referred to Vinik’s review, weight loss), and somnolence, leading to treatment of proliferative diabetic reti- summarizing a variety of agents used in high discontinuation rates (41). An im- nopathy. Diabetologia 30:199–207, 1987 treatment of painful diabetic neuropathy, portant approach is the use of combina- 4. Grant MB, Caballero S Jr: The potential reviewing for which ben- tion treatments; a recent trial showed that role of octreotide in the treatment of dia- efit has been reported, including car- use of and gabapentin together betic retinopathy. Treat Endocrinol 4: bemazepine, felbamate, gabapentin, is superior to either alone in individuals 199–203, 2005 , phenytoin, topiramate, and with neuropathic pain, with gabapentin 5. Grant MB, Mames RN, Fitzgerald C, Haz- (32). Newer approaches in- similar to placebo, although combination ariwala KM, Cooper-DeHoff R, Caballero clude the serotonin and norepinephrine treatment was associated with an in- S, Estes KS: The efficacy of octreotide in the therapy of severe nonproliferative and reuptake inhibitors duloxetine and ven- creased frequency of side effects, includ- early proliferative diabetic retinopathy: a lafaxine. Pain is transmitted by A and C ing constipation, dry mouth, and sedation randomized controlled study. Diabetes fibers. Serotonin and norepinephrine re- (42). For many patients, Tesfaye sug- Care 23:504–509, 2000 uptake inhibitors increase synaptic avail- gested, “the remedy is worse than the 6. Boehm BO, Lang GK, Jehle PM, Feldman ability of serotonin and norepinephine, disease,” so that we need to better under- B, Lang GE: Octreotide reduces vitreous

DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 763 Perspectives on the News

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