Correspondence
population with type 2 diabetes was compared with the obese population with normal glucose tolerance (rather than the total population); however, no such studies have been published up to now. Observed long-term data for the effects of bariatric surgery relative to conventional therapy on health-care use and costs are needed to confirm modelled results. So far, data from the Swedish Obese Subjects study show that in a 20-year period, healthcare use was similar or greater in the surgically treated group than in the conventionally treated group when all patients were analysed, including mostly patients without diabetes. 4 This comparison is likely to mask important differences that may exist for patients with impaired glucose or diabetes,5 which is an area requiring additional research. CK previously led an independent research grant from Allergan Australia. MN has received lecture and consulting fees from Abbott, Sanofi-Aventis, Itrim International, and Strategic Health Resources; research grants from Cambridge Weight Plan and Novo Nordisk; and royalty payments for coauthoring chapters in a Swedish textbook on obesity. AP declares no competing interests.
*Catherine Keating, Anna Peeters, Martin Neovius [email protected] Obesity and Population Health, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (CK, AP); Deakin Health Economics, Deakin University, Melbourne, VIC, Australia (CK); and Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden (MN) 1
2
3
4
5
Cummings DE, Cohen RV. Beyond BMI: the need for new guidelines governing the use of bariatric and metabolic surgery. Lancet Diabetes Endocrinol 2014; 2: 175–81. Keating CL, Dixon JB, Moodie ML, et al. Cost-effectiveness of surgically induced weight loss for the management of type 2 diabetes: modeled lifetime analysis. Diabetes Care 2009; 32: 567–74. Picot J, Jones J, Colquitt JL, et al. The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation. Health Technol Assess 2009; 13: 1–190, 215–357, iii–iv. Neovius M, Narbro K, Keating C, et al. Health care use during 20 years following bariatric surgery. JAMA 2012; 308: 1132–41. Maciejewski ML, Arterburn DE. Costeffectiveness of bariatric surgery. JAMA 2013; 310: 742–43.
The Series on bariatric surgery (February, 2014) brings the current management of morbid obesity into sharp focus. Alfons Pomp1 elegantly highlights the dangers associated with obesity and attempts to define some of the challenges of its treatment. He stresses that bariatric surgery is safe and effective in the management of obesity and its comorbid conditions. John Dixon and Jane Blazeby 2 eloquently explain the benefits for patient-perceived quality of life after surgery-induced weight loss. It has therefore been rightly questioned why bariatric surgery remains a last resort for the treatment of obesity. We wish to highlight another issue that has gone largely unnoticed— the huge gender disparity in the use of bariatric surgery. Despite similar rates of obesity in men and women at 24% and 26%, respectively, of 8794 bariatric surgical procedures performed in England in 2011–12 only 2081 (24%) were in men.3 This statistic is echoed globally. Although health-care use is universally higher by women than by men,4 little is known of the reasons underlying the gender inequality in the uptake of bariatric surgery. A perception of poorer outcomes of bariatric surgery in men among patients and the wider medical community might be one barrier to treatment. However, this view is clearly erroneous. Men generally present later in life, with more advanced obesity, and with more complex comorbidities,5 which might adversely affect outcomes. In our experience, however, there were no significant differences in weight loss and metabolic outcomes between men and women matched for six key baseline characteristics including age, BMI, type of bariatric procedure, presence of type 2 diabetes, insulin treatment, and treatment with continuous positive airway pressure for obstructive sleep apnoea (unpublished data). We call for further studies and urgent action to raise awareness and increase
www.thelancet.com/diabetes-endocrinology Vol 2 June 2014
acceptance of a potentially lifechanging intervention in this clinically disadvantaged group of patients. We declare no competing interests.
*Safwaan Adam, Akheel A Syed [email protected] Obesity Medicine and Endocrinology, Salford Royal NHS Foundation Trust and University Teaching Hospital, Salford M6 8HD, UK (SA, AAS); and University of Manchester, Manchester, UK (AAS) 1 2
3
4 5
Pomp A. Safety of bariatric surgery. Lancet Diabetes Endocrinol 2014; 2: 98–100. Dixon JB, Blazeby JM. Quality of life after bariatric surgery. Lancet Diabetes Endocrinol 2014; 2: 100–2. Health and Social Care Information Centre. Lifestyles statistics: statistics on obesity, physical activity and diet—England, 2013. Leeds: Health and Social Care Information Centre, 2013. Malcher G. The state of men’s health in Europe. BMJ 2011; 343: d7054. Farinholt GN, Carr AD, Chang EJ, Ali MR. A call to arms: obese men with more severe comorbid disease and underutilization of bariatric operations. Surg Endosc 2013; 27: 4556–63.
Subconjunctival bevacizumab for iris neovascularisation Antivascular endothelial growth factor injections have been increasingly used in the treatment of rubeosis and neovascular glaucoma, and several studies have reported regression of iris neovascularisation with intravitreal and intracameral bevacizumab. 1–2 The subconjuntival approach is less commonly reported and has more often been associated with treating disorders such as corneal neovascularisation.3 Rao and colleagues4 described the use of subconjunctival bevacizumab in a patient with ocular ischaemic syndrome and diabetic retinopathy. Bevacizumab is a 149 kDa full-length immunoglobulin G1 antibody, which is three times the molecular weight of ranibizumab (48 kDa). When injected subconjunctivally, bevacizumab has a direct transcleral route intraocularly or via conjunctival and lymphatic flow. Findings of animal studies have shown 449
Correspondence
that the maximum concentration of bevacizumab achieved in the iris and ciliary body is much higher when the drug is administered via the intravitreal (109 192·6 ng/g) than the subconjunctival (1418·7 ng/g) route.5 Why the authors chose to use the subconjunctival approach to give bevacizumab is not clear to us. If a subconjunctival approach was deemed preferable because of the presence of dense cataract restricting the view of the fundus, then presumably a smaller molecule such as ranibizumab would have had better ocular penetration. In animal studies, investigators detected high concentrations of both intravitreal and subconjunctival bevacizumab in the plasma. 5 The patient described in Rao and colleagues’ study had total occlusion of the right carotid artery and history of transient ischaemic attacks and could be at an increased risk of thromboembolic events after treatment with subconjuntival bevacizumab. Although subconjunctival bevacizumab might be useful as an interim treatment for rubeosis or neovascular glaucoma, most cases would need more definitive treatment such as retinal photocoagulation or glaucoma surgery. As described by Rao and co workers, the effect of subconjunctival bevacizumab was transient and three injections had to be given in the course of 6 months to sustain the beneficial effect. A more definitive option would be to consider glaucoma drainage devices or transcleral cyclophotocoagulation (if visual prognosis is deemed to be poor) once the intraocular pressure comes under control to avoid the systemic risks of repeated bevacizumab injections. We declare no competing interests.
*Vivien C Yip, Leonard W Yip, Augustinus Laude [email protected] National Healthcare Group Eye Institute, Tan Tock Seng Hospital, 308433, Singapore (VCY, LWY, AL)
450
1
2
3
4
5
Wakabayashi T, Oshima Y, Sakaguchi H, et al. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 2008; 115: 1571–80. Chalam KV, Gupta SK, Grover S, Brar VS, Agarwal S. Intracameral avastin dramatically resolves iris neovascularization and reverses neovascular glaucoma. Eur J Ophthalmol 2008; 18: 255–62. Zaki AA. Farid SF. Subconjunctival bevacizumab for corneal neovascularisation. Acta Ophthalmol 2010; 88: 868–71. Rao RC, Choudhry N, Apte RS. Regression of iris neovascularisation secondary to diabetic retinopathy with subconjunctival anti-VEGF therapy. Lancet Diabetes Endocrinol 2014; 2: 182. Hiroyuki N, Fumio S, Noriyuki K et al. Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits. Invest Ophthalmol Vis Sci 2009; 50: 4807–13.
Authors’ reply Yip and colleagues1 discuss the use of subconjunctival bevacizumab for iris neovascularisation in our patient with diabetic retinopathy and ocular ischaemic syndrome. The patient’s complete clinical history, some of which could not be included because of space restrictions, informed our decision-making process. The patient had posterior segment silicone oilfill after previous multiple diabetic tractional retinal detachment vitrectomy surgeries. Cataract and silicone oil-fill precluded intravitreal antivascular endothelial growth factor treatment, pan retinal photocoagulation, and pars plana placement of a glaucoma drainage device. The smaller molecular weight of ranibizumab versus bevacizumab might suggest that subconjunctival ranibizumab has better intraocular penetration. However, no report has described the comparative kinetics of intraocular penetration of these agents from the subconjunctival space in animal models or patients. Unexpectedly, despite its smaller size, ranibizumab was not as effective as bevacizumab in inducing corneal neovascularisation regression in rabbits. 1 Although the iris and ciliary body concentration of subconjunctival bevacizumab is
100 times less than intravitreal treatment, our case and another report of three cases showed regression of iris neovascularisation with subconjunctival bevacizumab treatment. 2 By contrast with the positive treatment response in these four patients, no report, to our knowledge, has described subconjunctival delivery of ranibizumab for iris neovascularisation—although we would predict ranibizumab to have a similar response. In the USA, ranibizumab is 40 times more expensive than bevacizumab. 3 Even if the patient had health insurance—which she did not—off-label use of subconjunctival ranibizumab for iris neovascularisation would need substantial out-of-pocket expense (roughly US$2000 per ranibizumab injection vs $50 for bevacizumab). The patient had previously tolerated many injections of intravitreal bevacizumab in her other eye as treatment for diabetic macular oedema without experiencing ocular or systemic complications. Injection of intracameral bevacizumab was considered, but the risk of hyphaema in view of florid iris neovascularisation was thought to be too high. The patient elected to proceed with subconjunctival bevacizumab treatment after discussion of the ocular and systemic risks of subjconjunctival and intracameral antivascular endothelial growth factor treatment, risk:benefit ratio of transcleral cyclophotocoagulation, cost of bevacizumab versus ranibizumab, and treatment history of the other eye. After being followed up for 6 months, investigators recorded partial regression of iris neovascularisation; the patient had no known ocular or system complications secondary to subconjunctival bevacizumab. Should the patient agree to consent, or if neovascular glaucoma became refractory to subconjunctival bevacizumab, we have not excluded future
www.thelancet.com/diabetes-endocrinology Vol 2 June 2014
population with type 2 diabetes was compared with the obese population with normal glucose tolerance (rather than the total population); however, no such studies have been published up to now. Observed long-term data for the effects of bariatric surgery relative to conventional therapy on health-care use and costs are needed to confirm modelled results. So far, data from the Swedish Obese Subjects study show that in a 20-year period, healthcare use was similar or greater in the surgically treated group than in the conventionally treated group when all patients were analysed, including mostly patients without diabetes. 4 This comparison is likely to mask important differences that may exist for patients with impaired glucose or diabetes,5 which is an area requiring additional research. CK previously led an independent research grant from Allergan Australia. MN has received lecture and consulting fees from Abbott, Sanofi-Aventis, Itrim International, and Strategic Health Resources; research grants from Cambridge Weight Plan and Novo Nordisk; and royalty payments for coauthoring chapters in a Swedish textbook on obesity. AP declares no competing interests.
*Catherine Keating, Anna Peeters, Martin Neovius [email protected] Obesity and Population Health, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (CK, AP); Deakin Health Economics, Deakin University, Melbourne, VIC, Australia (CK); and Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden (MN) 1
2
3
4
5
Cummings DE, Cohen RV. Beyond BMI: the need for new guidelines governing the use of bariatric and metabolic surgery. Lancet Diabetes Endocrinol 2014; 2: 175–81. Keating CL, Dixon JB, Moodie ML, et al. Cost-effectiveness of surgically induced weight loss for the management of type 2 diabetes: modeled lifetime analysis. Diabetes Care 2009; 32: 567–74. Picot J, Jones J, Colquitt JL, et al. The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation. Health Technol Assess 2009; 13: 1–190, 215–357, iii–iv. Neovius M, Narbro K, Keating C, et al. Health care use during 20 years following bariatric surgery. JAMA 2012; 308: 1132–41. Maciejewski ML, Arterburn DE. Costeffectiveness of bariatric surgery. JAMA 2013; 310: 742–43.
The Series on bariatric surgery (February, 2014) brings the current management of morbid obesity into sharp focus. Alfons Pomp1 elegantly highlights the dangers associated with obesity and attempts to define some of the challenges of its treatment. He stresses that bariatric surgery is safe and effective in the management of obesity and its comorbid conditions. John Dixon and Jane Blazeby 2 eloquently explain the benefits for patient-perceived quality of life after surgery-induced weight loss. It has therefore been rightly questioned why bariatric surgery remains a last resort for the treatment of obesity. We wish to highlight another issue that has gone largely unnoticed— the huge gender disparity in the use of bariatric surgery. Despite similar rates of obesity in men and women at 24% and 26%, respectively, of 8794 bariatric surgical procedures performed in England in 2011–12 only 2081 (24%) were in men.3 This statistic is echoed globally. Although health-care use is universally higher by women than by men,4 little is known of the reasons underlying the gender inequality in the uptake of bariatric surgery. A perception of poorer outcomes of bariatric surgery in men among patients and the wider medical community might be one barrier to treatment. However, this view is clearly erroneous. Men generally present later in life, with more advanced obesity, and with more complex comorbidities,5 which might adversely affect outcomes. In our experience, however, there were no significant differences in weight loss and metabolic outcomes between men and women matched for six key baseline characteristics including age, BMI, type of bariatric procedure, presence of type 2 diabetes, insulin treatment, and treatment with continuous positive airway pressure for obstructive sleep apnoea (unpublished data). We call for further studies and urgent action to raise awareness and increase
www.thelancet.com/diabetes-endocrinology Vol 2 June 2014
acceptance of a potentially lifechanging intervention in this clinically disadvantaged group of patients. We declare no competing interests.
*Safwaan Adam, Akheel A Syed [email protected] Obesity Medicine and Endocrinology, Salford Royal NHS Foundation Trust and University Teaching Hospital, Salford M6 8HD, UK (SA, AAS); and University of Manchester, Manchester, UK (AAS) 1 2
3
4 5
Pomp A. Safety of bariatric surgery. Lancet Diabetes Endocrinol 2014; 2: 98–100. Dixon JB, Blazeby JM. Quality of life after bariatric surgery. Lancet Diabetes Endocrinol 2014; 2: 100–2. Health and Social Care Information Centre. Lifestyles statistics: statistics on obesity, physical activity and diet—England, 2013. Leeds: Health and Social Care Information Centre, 2013. Malcher G. The state of men’s health in Europe. BMJ 2011; 343: d7054. Farinholt GN, Carr AD, Chang EJ, Ali MR. A call to arms: obese men with more severe comorbid disease and underutilization of bariatric operations. Surg Endosc 2013; 27: 4556–63.
Subconjunctival bevacizumab for iris neovascularisation Antivascular endothelial growth factor injections have been increasingly used in the treatment of rubeosis and neovascular glaucoma, and several studies have reported regression of iris neovascularisation with intravitreal and intracameral bevacizumab. 1–2 The subconjuntival approach is less commonly reported and has more often been associated with treating disorders such as corneal neovascularisation.3 Rao and colleagues4 described the use of subconjunctival bevacizumab in a patient with ocular ischaemic syndrome and diabetic retinopathy. Bevacizumab is a 149 kDa full-length immunoglobulin G1 antibody, which is three times the molecular weight of ranibizumab (48 kDa). When injected subconjunctivally, bevacizumab has a direct transcleral route intraocularly or via conjunctival and lymphatic flow. Findings of animal studies have shown 449
Correspondence
that the maximum concentration of bevacizumab achieved in the iris and ciliary body is much higher when the drug is administered via the intravitreal (109 192·6 ng/g) than the subconjunctival (1418·7 ng/g) route.5 Why the authors chose to use the subconjunctival approach to give bevacizumab is not clear to us. If a subconjunctival approach was deemed preferable because of the presence of dense cataract restricting the view of the fundus, then presumably a smaller molecule such as ranibizumab would have had better ocular penetration. In animal studies, investigators detected high concentrations of both intravitreal and subconjunctival bevacizumab in the plasma. 5 The patient described in Rao and colleagues’ study had total occlusion of the right carotid artery and history of transient ischaemic attacks and could be at an increased risk of thromboembolic events after treatment with subconjuntival bevacizumab. Although subconjunctival bevacizumab might be useful as an interim treatment for rubeosis or neovascular glaucoma, most cases would need more definitive treatment such as retinal photocoagulation or glaucoma surgery. As described by Rao and co workers, the effect of subconjunctival bevacizumab was transient and three injections had to be given in the course of 6 months to sustain the beneficial effect. A more definitive option would be to consider glaucoma drainage devices or transcleral cyclophotocoagulation (if visual prognosis is deemed to be poor) once the intraocular pressure comes under control to avoid the systemic risks of repeated bevacizumab injections. We declare no competing interests.
*Vivien C Yip, Leonard W Yip, Augustinus Laude [email protected] National Healthcare Group Eye Institute, Tan Tock Seng Hospital, 308433, Singapore (VCY, LWY, AL)
450
1
2
3
4
5
Wakabayashi T, Oshima Y, Sakaguchi H, et al. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 2008; 115: 1571–80. Chalam KV, Gupta SK, Grover S, Brar VS, Agarwal S. Intracameral avastin dramatically resolves iris neovascularization and reverses neovascular glaucoma. Eur J Ophthalmol 2008; 18: 255–62. Zaki AA. Farid SF. Subconjunctival bevacizumab for corneal neovascularisation. Acta Ophthalmol 2010; 88: 868–71. Rao RC, Choudhry N, Apte RS. Regression of iris neovascularisation secondary to diabetic retinopathy with subconjunctival anti-VEGF therapy. Lancet Diabetes Endocrinol 2014; 2: 182. Hiroyuki N, Fumio S, Noriyuki K et al. Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits. Invest Ophthalmol Vis Sci 2009; 50: 4807–13.
Authors’ reply Yip and colleagues1 discuss the use of subconjunctival bevacizumab for iris neovascularisation in our patient with diabetic retinopathy and ocular ischaemic syndrome. The patient’s complete clinical history, some of which could not be included because of space restrictions, informed our decision-making process. The patient had posterior segment silicone oilfill after previous multiple diabetic tractional retinal detachment vitrectomy surgeries. Cataract and silicone oil-fill precluded intravitreal antivascular endothelial growth factor treatment, pan retinal photocoagulation, and pars plana placement of a glaucoma drainage device. The smaller molecular weight of ranibizumab versus bevacizumab might suggest that subconjunctival ranibizumab has better intraocular penetration. However, no report has described the comparative kinetics of intraocular penetration of these agents from the subconjunctival space in animal models or patients. Unexpectedly, despite its smaller size, ranibizumab was not as effective as bevacizumab in inducing corneal neovascularisation regression in rabbits. 1 Although the iris and ciliary body concentration of subconjunctival bevacizumab is
100 times less than intravitreal treatment, our case and another report of three cases showed regression of iris neovascularisation with subconjunctival bevacizumab treatment. 2 By contrast with the positive treatment response in these four patients, no report, to our knowledge, has described subconjunctival delivery of ranibizumab for iris neovascularisation—although we would predict ranibizumab to have a similar response. In the USA, ranibizumab is 40 times more expensive than bevacizumab. 3 Even if the patient had health insurance—which she did not—off-label use of subconjunctival ranibizumab for iris neovascularisation would need substantial out-of-pocket expense (roughly US$2000 per ranibizumab injection vs $50 for bevacizumab). The patient had previously tolerated many injections of intravitreal bevacizumab in her other eye as treatment for diabetic macular oedema without experiencing ocular or systemic complications. Injection of intracameral bevacizumab was considered, but the risk of hyphaema in view of florid iris neovascularisation was thought to be too high. The patient elected to proceed with subconjunctival bevacizumab treatment after discussion of the ocular and systemic risks of subjconjunctival and intracameral antivascular endothelial growth factor treatment, risk:benefit ratio of transcleral cyclophotocoagulation, cost of bevacizumab versus ranibizumab, and treatment history of the other eye. After being followed up for 6 months, investigators recorded partial regression of iris neovascularisation; the patient had no known ocular or system complications secondary to subconjunctival bevacizumab. Should the patient agree to consent, or if neovascular glaucoma became refractory to subconjunctival bevacizumab, we have not excluded future
www.thelancet.com/diabetes-endocrinology Vol 2 June 2014
