CLINICAL COURSE OF DIABETIC RETINOPATHY IN KOREAN TYPE 2 DIABETES AFTER BARIATRIC SURGERY A Pilot Study YONG JOON KIM, MD,* DU RI SEO, MD,* MYUNG JIN KIM, MD,† SUNG JIN LEE, MD,* KYUNG YUL HUR, MD,† KYUNG SEEK CHOI, MD* Purpose: To assess the changes in diabetic retinopathy (DR) in Type 2 diabetes (T2DM) patients after bariatric surgery. Methods: Consecutive 20 patients with T2DM who underwent bariatric surgery and were followed for at least 12 months were enrolled. The case history was reviewed retrospectively, and laboratory data were assessed at baseline and every 3 months postoperatively. Two retinal specialists evaluated the severity of DR with dilated fundus examination preoperatively and postoperatively. Factors associated with DR progression were assessed. Results: During the follow-up period, 2 of 12 patients without DR and 2 of 3 patients with mild nonproliferative DR before surgery developed moderate nonproliferative DR. All five patients with moderate nonproliferative DR or worse preoperatively had progression requiring intervention. Preexisting DR (P = 0.005) and albuminuria (P = 0.01) were identified as associated with DR progression. Six patients (30%) entered remission of T2DM, but remission of T2DM could not halt the DR progression. Conclusion: Diabetic retinopathy progression can occur in patients with or without before DR after bariatric surgery, regardless of remission of T2DM. All patients with T2DM should be examined regularly by an ophthalmologist postoperatively, and more carefully patients with previous DR or albuminuria. RETINA 35:935–943, 2015
D
achieved glycemic control in significantly more patients than intensive medical therapy alone. In this randomized controlled trial, remission of diabetes, which was defined as a glycated hemoglobin level #6.0% without medication, occurred in 21 of 50 patients (42%) 12 months after gastric bypass surgery.7 Glycated hemoglobin levels were decreased markedly at 3 months postoperatively. This rapid improvement is the main advantage of bariatric surgery. Several studies have reported that a rapid change in glycemic control can result in a paradoxical deterioration of DR.9,10 Although the glycated hemoglobin level was improved, more than half of the patients required oral hypoglycemic agents after bariatric surgery. Therefore, rapid progression of DR might occur in patients who undergo bariatric surgery. However, the remission of diabetes is a novel clinical situation in T2DM treatment.7,8 The clinical course of DR after
iabetic retinopathy (DR) is the leading cause of legal blindness in developed countries.1,2 In Type 2 diabetes (T2DM), .25% of patients develop DR within 2 years of diagnosis.3 Intensive medical therapy can delay the progression of DR, but only about a half of patients achieve sufficient glycemic control.4–6 Bariatric surgery has been performed widely as a metabolic surgery to treat poorly controlled diabetes.7,8 The Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial showed that bariatric surgery plus medical therapy From the Departments of *Ophthalmology, and †Surgery, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea. Supported by the Soonchunhyang University Research Fund. None of the authors have any conflicting interests to disclose. Reprint requests: Kyung Seek Choi, MD, Department of Ophthalmology, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, 59, Daesagwan-ro, Yongsan-gu, Seoul 140-743, Korea; e-mail: [email protected]
935
936
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 5
remission of diabetes is seldom reported. Considering the growing number of patients who have undergone bariatric surgery, this should be addressed. Therefore, the aim of this retrospective study primarily was to evaluate the clinical course of DR in patients with T2DM who underwent bariatric surgery. Risk factors associated with the progression of DR were also analyzed. Methods Consecutive patients who underwent bariatric surgery for T2DM treatment between September 2009 and March 2013 were enrolled. The medical records of the patients who met the following inclusion criteria were reviewed retrospectively: 1) preoperative evaluation within 3 months before bariatric surgery; 2) postoperative follow-up for at least 12 months; and 3) the absence of retinal vascular disease except DR. The research adhered to the tenets of the Declaration of Helsinki. The institutional review board/ethics committee approval was obtained for this retrospective study, and informed consent was obtained from all participants before bariatric surgery. Bariatric Surgery All patients underwent laparoscopic singleanastomosis gastric bypass with the five-trocar method performed by a single experienced team (M.J.K. and K.Y.H.). The details of the surgical procedure have been described elsewhere.11 The antidiabetic effect of laparoscopic single-anastomosis gastric bypass in Korean patients with T2DM was also reported previously.11–13 Ophthalmic Examinations All patients underwent an ophthalmic examination preoperatively, which included the corrected distance visual acuity, slit-lamp biomicroscopy, tonometry, fundus photography, and a dilated fundus examination. The same ophthalmic examinations were performed at every 3 months postoperatively. All ophthalmic examinations were performed by two experienced retinal specialists (S.J.L. and K.S.C.). Based on the physician’s decision, optical coherence tomography and fluorescein angiography (Spectralis HRA + optical coherence tomography; Heidelberg Engineering, Dossenheim, Germany) were performed to evaluate the severity of DR.
and laboratory values. We also assessed the body mass index (BMI), glycated hemoglobin and fasting glucose levels, cholesterol profile, and renal function profile at baseline and every 3 months postoperatively. Outcome Measures The main outcome measure was the clinical course of DR after bariatric surgery. Diabetic retinopathy severity was classified based on the clinical records, fundus color photographs, optical coherence tomography, and fluorescein angiography according to the international clinical DR and diabetic macular edema severity scale proposed by the Global Diabetic Retinopathy Project Group.14 Progression of DR was defined as either 1) an increase in severity or 2) the development of vitreous hemorrhage or diabetic macular edema requiring intervention. Secondary outcome measures were corrected distance visual acuity, intraocular pressure, BMI, laboratory data, and changes in medications. The T2DM remission rate was also assessed. Remission of diabetes was defined as the maintenance of a glycated hemoglobin level #6.0% without oral hypoglycemic agents or insulin after surgery.7 The latest laboratory results were used as the postoperative values in the statistical analysis. The Study Groups The patients were divided into two groups: the progression group consisted of patients with DR progression after bariatric surgery and the nonprogression group comprised of patients with no DR progression. Statistical Analysis All statistical analyses were performed with SPSS version 19.0 (SPSS, an IBM company, Chicago, IL). Preoperative and postoperative values for the same group were compared with Wilcoxon’s signed-rank test. The Mann–Whitney U test and Fisher’s exact test were used to compare the two groups. Binomial logistic regression analysis was performed to identify factors associated with the progression of DR. The odds ratio of the factors detected in the univariate analysis and their 95% confidence intervals were calculated. A value of P , 0.05 was considered to indicate statistical significance. Results
Other Data Collections and Assessment
Study Population
At baseline, we collected data on demographic information, coexisting diseases, use of medications,
Twenty-eight patients underwent bariatric surgery and eligible preoperative evaluation. One patient (no
CHANGES IN DR AFTER BARIATRIC SURGERY KIM ET AL
937
Three of 6 patients were in the nonprogression group and had no DR preoperatively and postoperatively. The other three were in the progression group. These patients entered remission of T2DM within 6 months after surgery, and DR progressed after the remission of T2DM (Table 2; Patients 2, 8, and 9).
DR preoperatively) had branch retinal vein occlusion, and seven patients received postoperative follow-up in local hospitals. Of these patients, three had no DR, two had mild nonproliferative DR (NPDR), one had severe NPDR, and one had proliferative DR preoperatively. These 8 patients were therefore excluded, whereas the remaining 20 patients met the inclusion criteria and were included in the analysis. Of the 20 patients, 9 patients (45%) had DR progression after bariatric surgery and were divided into progression group. Eleven patients (55%) were in the nonprogression group. The median follow-up duration was 28.0 months (interquartile range [IQR], 13.5–42.5 months) in the progression group and 26.0 months (IQR, 13.0– 36.0 months) in the nonprogression group (P = 0.84). The details of demographic characteristics of patients before bariatric surgery are presented in Table 1.
Changes in Other Clinical Data After Bariatric Surgery All patients (40 eyes) had a corrected distance visual acuity of 20/40 or better before bariatric surgery. No patient in the nonprogression group had visual loss during the follow-up period. In the progression group, seven patients had a visual loss of 3 or more Snellen lines (Patients 2–8). Only Patient 3, who had proliferative DR before surgery, developed neovascular glaucoma in the right eye postoperatively. Despite Ahmed glaucoma valve implantation, this patient subsequently developed legal blindness. Except for the right eye of Patient 3, none of the eyes had a high intraocular pressure preoperatively or postoperatively. Of overall 20 patients, none of the patients had uncontrolled hypertension (HTN). The median postoperative BMI, glycated hemoglobin level, and fasting glucose level were 22.5 kg/m2 (IQR, 21.1– 23.6 kg/m2), 7.0% (IQR, 5.9–7.8%), and 112.0 mg/dL (IQR 104.5–132.0 mg/dL) in the progression group, and 23.4 kg/m2 (IQR, 21.6–24.1 kg/m2), 6.7% (IQR, 5.6–9.4%), and 131.0 mg/dL (IQR 109.0– 179.0 mg/dL) in the nonprogression group, respectively. These values were significantly lower than the preoperative values (P , 0.01 for all). The median postoperative serum total cholesterol level and creatinine level were 168.0 mg/dL (IQR, 148.0–206.5 mg/dL) and 0.86 mg/dL (IQR, 0.72– 1.15 mg/dL) in the progression group, and 164.0 mg/dL (IQR, 152.0–199.0 mg/dL) and 0.60 mg/dL (IQR, 0.54–0.66 mg/dL) in the nonprogression group, respectively. The differences were not
Clinical Course of Diabetic Retinopathy After Bariatric Surgery In the nonprogression group, 10 patients had no DR before surgery and only 1 patient had preexisting mild NPDR. Diabetic retinopathy regression was not observed in any patient during the study period. In the progression group, two patients had no DR before surgery and seven patients had preexisting DR. Three patients had mild NPDR, two had moderate NPDR, and further three patients had severe NPDR or proliferative DR. Among them, five patients underwent progression of DR requiring intervention. The preoperative and postoperative severities of DR in the progression group are shown in Table 2. Representative clinical cases are presented in Figures 1 and 2. Diabetic Retinopathy in Remitted Diabetes After Bariatric Surgery Six (30%) entered remission of T2DM postoperatively and maintained a glycated hemoglobin level #6.0% without oral hypoglycemic agents or insulin.
Table 1. Demographic Characteristics of Study Population Before the Bariatric Surgery Total (N = 20) Age (years) Female, n (%) BMI (kg/m2) Duration of DM (years) Hypertension, n (%) Medication, n (%) OHA only Insulin ± OHA
50.5 14 25.4 10.0 7
(37.5–57.0) (70) (22.4–28.2) (5.0–14.8) (35)
15 (75) 5 (25)
Values are median (IQR) or N (%). Mann–Whitney U test or Fisher’s exact test. DM, diabetes mellitus; OHA, oral hypoglycemic agent.
Progression (N = 9) 53.0 5 24.5 10.0 5
(38.0–61.0) (55.6) (21.1–28.1) (7.5–22.0) (55.6)
6 (66.7) 3 (33.3)
Nonprogression (N = 11) 44.0 9 25.9 5.0 2
(37.0–53.0) (81.8) (23.2–28.5) (4.0–10.0) (18.2)
9 (81.8) 2 (18.2)
P 0.295 0.336 0.456 0.067 0.160 0.617
Preoperative Data
1
2
3
4
61
42
61
53
F
F
M
M
DM Duration (years) 10
10
20
20
Preoperative HTN Medication +
−
+
−
OHA
OHA
OHA + I
OHA
BMI (kg/ m2)
HbA1c (%)
28.2
11.3
24.0
20.1
22.1
8.8
7.8
9.3
AU (mg/ day)
BMI (kg/ m2)
HbA1c (%)
132.2
22.0
7.0
88.9
44.5
39.6
20.3
23.0
21.8
5.7
6.5
7.3
AU (mg/ day) 122.3
412.1
25.3
38.8
Severity of DR
Eye R
Mild NPDR
L
Mild NPDR
R
No DR
L
No DR
R
PDR, s/p PRP
L
PDR, s/p PRP
R
R L R L R
Moderate NPDR Moderate NPDR PDR, s/p PRP PDR, s/p PRP Severe NPDR Severe NPDR Mild NPDR
L
Mild NPDR
R
R
Moderate NPDR Moderate NPDR No DR
L
No DR
L 5
57
F
5
−
I
19.4
12.9
2,314.0
19.8
8.0
2,315.0
6
30
F
10
+
OHA
25.4
7.6
15.3
22.5
7.3
15.1
7
51
F
24
+
OHA
26.0
9.4
1,419.9
24.1
7.7
0.3
8
63
M
27
+
I
31.1
6.4
5,167.2
22.6
6.0
2,262.7
L 9
34
M
3
−
OHA
28.1
11.1
72.8
24.5
5.8
4.7
Preoperative
Last F/U Moderate NPDR Moderate NPDR Moderate NPDR Moderate NPDR PDR, NVG
Tx None
F/U (months) 46
None None
30
None AGV, implant STTA
PDR, moderate DME PDR, VH PRP PDR
PRP
PDR, VH PDR, VH PDR, VH PDR, VH Severe NPDR Severe NPDR PDR
PRP TPPV IVBI IVBI None
PDR
PRP
Moderate NPDR Moderate NPDR
None
42
43
12 22 28
None PRP
14
13
None
(+), positive; (−), negative; AGV, Ahmed glaucoma valve; AU, albuminuria; DM, diabetes mellitus; DME, diabetic macular edema; F, female; F/U, follow-up duration; HbA1c, glycated hemoglobin; I, insulin; IVBI, intravitreal bevacizumab injection; L, left; M, male; NVG, neovascular glaucoma; OHA, oral hypoglycemic agent; PDR, proliferative diabetic retinopathy; PRP, panretinal photocoagulation; R, right; STTA, sub-Tenon triamcinolone acetonide injection; TPPV, trans pars plana vitrectomy; Tx, treatment; VH, vitreous hemorrhage.
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 5
Age No. (years) Sex
Postoperative Data
938
Table 2. Clinical Courses of Nine Patients Who Underwent Progression of DR After Bariatric Surgery
CHANGES IN DR AFTER BARIATRIC SURGERY KIM ET AL
939
Fig. 1. The clinical course of DR of Patient 6. At the time of surgery, both eyes of the patient had severe NPDR. No evidence of neovascularization was detected with either dilated fundus examination or fluorescein angiography (A and B). Neovascularization and vitreous hemorrhage developed in both eyes 8 months after the bariatric surgery (C and D). Because this young patient did not want to undergo laser therapy, each eye was treated with a single intravitreal injection of bevacizumab. No significant vitreous hemorrhage or diabetic macular edema occurred over the next 12 months.
significant compared with the preoperative values (Table 3). All patients in both groups revealed the normal serum creatinine level preoperatively and postoperatively. Eight of the nine patients in the progression group had albuminuria before surgery. The urinary albumin level improved in six patients in the progression group. The number of patients with albuminuria decreased from eight to five without any developing new albuminuria in the progression group. Three of 11 patients in the nonprogression group had microalbuminuria (30–300 mg/day) before surgery. None of the patients in the nonprogression group had albuminuria postoperatively.
progression. Age, coexisting HTN, the use of insulin, BMI, glycated hemoglobin level, total cholesterol level before bariatric surgery, and remission of T2DM were not associated with the progression of DR in the univariate analyses. The duration of T2DM increased the odds of DR progression with borderline significance (P = 0.05) but was not significant in the multivariate analysis (P = 0.16). Preexisting DR and albuminuria were identified as significant risk factors in both univariate and multivariate analyses. The detailed results of the univariate logistic regression of each factor are presented in Table 3.
Discussion Factors Associated With Progression of Diabetic Retinopathy The odds ratio and 95% confidence intervals were used to identify the factors associated with DR
Observational studies have suggested that bariatric surgery can improve or halt the development of microvascular complications such as diabetic nephropathy and retinopathy.15–17 Suggested weight-dependent
940
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 5
Fig. 2. The clinical course of DR of Patient 9. A 34-year-old man with uncontrolled diabetes had taken an oral hypoglycemic agent for 3 years preoperatively. He had an HbA1c of 11.1% and microalbuminuria, but no evidence of DR was detected by dilated fundus examination at the time of surgery (A and B). Remission of diabetes was evident based on the HbA1c level and oral glucose tolerance test 3 months postoperatively. Remission of microalbuminuria also occurred within 6 months. However, NPDR developed and progressed rapidly to moderate NPDR (C–F) 9 months after surgery.
and weight-independent mechanisms underlying the antidiabetic impact of bariatric surgery included 1) enhanced nutrient stimulation of lower intestinal hormones (e.g., glucagon-like Peptide 1); 2) altered physiology by excluding ingested nutrients from the upper intestine, compromised ghrelin secretion; 3) the modulation of intestinal nutrient sensing and regulation of insulin sensitivity; and 4) other changes not yet characterized fully.18 A marked improvement in
the index for homeostasis model assessment of insulin resistance, which might be linked to be the attenuation of chronic inflammation, has been reported after bariatric surgery.7 Bariatric surgery can lead to a rapid significant improvement in glycemic control in T2DM. Although intense glycemic control can delay the onset and progression of DR, a rapid change in glycemic control might also result in the paradoxical progression of
CHANGES IN DR AFTER BARIATRIC SURGERY KIM ET AL
941
Table 3. Factors Associated With Progression of DR After the Bariatric Surgery Factors Age (years) DM duration (years) Coexisting HTN, n (%) Insulin ± OHA Preexisting DR Albuminuria ($30 mg/day) BMI (kg/m2) Glycated hemoglobin (%) Fasting glucose (mg/dL) Total cholesterol (mg/dL) DM remission after surgery, n (%)
Progression (N = 9) 53.0 10.0 5 5 7 8 24.5 9.3 184.0 199.0 3
(38.0–61.0) (7.5–22.0) (55.6) (55.6) (77.8) (88.9) (21.1–28.2) (7.7–11.2) (145.5–279.0) (168.0–249.0) (33.3)
Nonprogression (N = 11) 44.0 5.0 2 3 1 3 25.9 9.5 211.0 174.0 3
(37.0–53.0) (4.0–10.0) (18.2) (27.3) (9.1) (27.3) (23.2–28.5) (8.3–10.5) (173.0–258.0) (138.0–199.0) (27.3)
OR
95% CI
P
1.0 1.2 5.6 2.3 31.5 21.3 0.9 0.9 1.0 1.0 1.3
0.962–1.123 0.998–1.412 0.747–42.359 0.285–17.759 2.350–422.299 1.811–251.264 0.715–1.141 0.579–1.472 0.985–1.014 0.993–1.028 0.196–9.083
0.333 0.052 0.160 0.617 0.005* 0.010* 0.393 0.737 0.898 0.250 1.000
Values are median (IQR) or N (%). *P , 0.05; univariate logistic regression. CI, confidence interval; DM, diabetes mellitus; OHA, oral hypoglycemic agent; OR, odds ratio.
DR.9,10 One possible mechanism of the paradoxical progression is an insulin-like growth factor 1 (IGF1)-induced cascade of intracellular signaling.16 The serum IGF-1 level is negatively correlated with the glucose level. A rapid improvement in glycemic control up-regulates the serum level of IGF-1, a potent angiogenic and mitogenic hormone.19 If the retina is damaged sufficiently through hypoxia, the upregulated IGF-1 might promote the progression of DR. The induction of endoplasmic reticulum stress through the shift from high to low normal glucose was also postulated as a mechanism of the paradoxical progression.16 This can result in the inflammation of retinal pericytes and deteriorate the autoregulation of the retinal circulation.20 A few studies have reported the changes in DR after bariatric surgery. Varadhan et al17 reported the changes in 23 patients: 2 (9%) developed new DR, whereas 2 others (9%) had progression of preexisting DR. They also reported the postoperative regression of DR in 2 patients (9%). Thomas et al16 assessed the changes in DR in 38 patients after the bariatric surgery and reported that 26 (68.4%) had no change in DR status, 5 (13.2%) had apparent regression of DR, and 7 (18.4%) had progression of DR. Of the 7 patients who had DR progression, 4 patients with no DR preoperatively developed only 1 or 2 microaneurysms; 1 patient with 7 microaneurysms and 1 blot hemorrhage before surgery had .20 microaneurysms and 8 blot hemorrhages postoperatively; another patient with small venous loops and intraretinal microvascular abnormalities before surgery had additional hard exudates at the fovea; and the last patient with exudative maculopathy had additional microaneurysms and hemorrhage postoperatively. However, previous studies have critical shortcomings. These studies used only standardized digital photographs to assess the severity
of DR without a dilated fundus examination. The severity of DR cannot be assessed precisely with the status of the posterior pole, and the disappearance of one or two microaneurysms at the posterior pole does not indicate the regression of DR. Furthermore, Thomas et al16 assessed the DR progression using self-proposed severity scales, which are not used widely in ophthalmology. Silva et al21 reported the case of a white female who suffered rapid worsening DR within 1 month of the bariatric surgery. This patient had very severe NPDR preoperatively. The glycated hemoglobin level decreased from 8.8% to 7.2%, but she underwent diabetic vitrectomy because of a vitreous hemorrhage and tractional retinal detachment at 3.5 months after the bariatric surgery. In this study, we assessed primarily the severity of DR and progression of DR according to the disease severity scale proposed by the Global Diabetic Retinopathy Project Group.14 No patient revealed regression of DR. Two patients with mild NPDR preoperatively progressed to moderate NPDR. All five patients with moderate or more severe NPDR preoperatively had progression that required intervention (Table 2). Preexisting DR and albuminuria were identified as factors significantly associated with DR progression. We think that these findings in the patients with moderate or more severe NPDR were related to the up-regulation of IGF-1 after bariatric surgery. Two patients with no previous DR developed moderate NPDR 30 months and 13 months postoperatively, respectively. Both of them had microalbuminuria preoperatively, which suggests that subclinical diabetic changes might have occurred in their retinas before the bariatric surgery.22,23 The proportion and severity of DR progression in this study were greater and more severe than reported previously.16,17 These differences might be explained
942
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 5
by several factors. First, the follow-up period was longer in our study. Second, the higher glycated hemoglobin level (9.6%) before surgery might have contributed to the results (8.2 and 7.9% in the 2 previous studies). However, the preoperative glycated hemoglobin level did not show a significant association with DR progression in our or another study.16 Third, the characteristics of Korean T2DM patients might explain the differences: they have weaker pancreatic islet cells and are more susceptible to insulin resistance than other ethnic groups.11 They also have a lower mean BMI, which might weaken the weightdependent antidiabetic effect of the surgery.12 However, the preoperative BMI was not associated with disease progression or glycemic control in this study and other randomized controlled trials.24 We also assessed the changes in DR in patients who entered remission of T2DM. The postoperative T2DM remission rate was 30% (6 patients) in our series, which was comparable with published reports.7,11,13 Three of the six patients with remission of T2DM had progression of DR, and two of them had no DR preoperatively. Our study showed that the remission of T2DM could not halt the development or progression of DR. Regarding secondary outcome measures, bariatric surgery significantly influenced BMI, glycemic control, and microalbuminuria, but not total cholesterol. These have been identified in several prospective studies with long-term follow-up.8,15 Coexisting HTN did not show a significant association with DR progression in our study. However, the association between blood pressure and DR progression should be reevaluated because no patient had uncontrolled HTN. Unlike DR, none of the 9 patients with no albuminuria before surgery developed microalbuminuria postoperatively, and 9 of the 11 patients with albuminuria benefited from the bariatric surgery in terms of the urine albumin level. The dissociation of the changes in retinopathy and nephropathy after bariatric surgery in patients with T2DM is a novel finding of our study. We speculate that it is related to the difference in the pathogenesis of the two major microvascular complications of diabetes. The key pathophysiologic events in diabetic nephropathy are alteration in the molecular structure of the components of the glomerulus and its basement membrane caused by hyperglycemia-induced glycosylation of tissue protein, and intraglomerular HTN.25–28 Hyperglycemia-induced damage is also important in the development of DR. Hyperglycemia causes apoptosis of retinal capillary pericytes through intracellular cascade signaling, which leads to weakness in the capillary walls, aneurysm formation, fluid leakage, impaired vascular function, and ultimately ischemia
and infarction of the retina.25,29 The damaged retina itself releases vasoproliferative factors, which can induce further retinal damage, including neovascularization independently of hyperglycemia.30 There are several limitations to this study. In Asia, T2DM tends to occur in patients with a relatively lower BMI compared with western countries.12 Our patients had chosen to receive bariatric surgery as a metabolic surgery, rather than for obesity. Therefore, the results may not be directly comparable with western T2DM patients who are in the obese range. The retrospective design and few patients are further limitations. Moreover, 8 of 28 patients were excluded from the analysis. Because there are few medical centers in Korea capable of performing the metabolic surgery during the study period, seven patients were referred to our hospital for the bariatric surgery and received postoperative follow-up in their local hospitals. Therefore, conclusions cannot be drawn from this series regarding the exact rates of DR progression after the bariatric surgery at this time. Nevertheless, there are several strengths of this investigation above and beyond previously published data. First, this is the first study to evaluate the progression of DR after bariatric surgery based on the results of detailed ophthalmic examinations and a general severity scale. Regression of DR was not observed in any patient in this study. Second, the dissociation of the changes in retinopathy and nephropathy is the novel finding of this study, which was not addressed in the previous investigations. Third, we evaluated the risk factors for DR progression and demonstrated that the development and progression of DR can occur even in patients who show remission of diabetes or in patients without previous DR after the bariatric surgery. The result of this pilot study warrants the further prospective investigations involving a greater number of patients. In conclusion, physicians should be aware of possible DR progression after bariatric surgery and should educate their patients about this. All patients with T2DM who undergo the bariatric surgery should have regular follow-up, regardless of the severity of previous DR or remission of diabetes. Key words: bariatric surgery, clinical course, diabetic retinopathy. References 1. Fong DS, Aiello LP, Ferris FL III, Klein R. Diabetic retinopathy. Diabetes Care 2004;27:2540–2553. 2. Zhang X, Saaddine JB, Chou CF, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA 2010;304: 649–656.
CHANGES IN DR AFTER BARIATRIC SURGERY KIM ET AL 3. Fong DS, Aiello L, Gardner TW, et al. Retinopathy in diabetes. Diabetes Care 2004;27:S84–S87. 4. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: 837–853. 5. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977–986. 6. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004;291:335–342. 7. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med 2012;366:1567–1576. 8. Sjostrom L, Lidroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Eng J Med 2004;351:2683–2693. 9. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology 1995;102:647–661. 10. Brooks AM, Lissett CA. A dramatic deterioration in diabetic retinopathy with improvement in glycated hemoglobin (HbA (1c)) on exenatide treatment. Diabet Med 2009;26:190. 11. Kim MJ, Hur KY. Short-term outcomes of laparoscopic single anastomosis gastric bypass (LSAGB) for the treatment of type 2 diabetes in lower BMI (,30 kg/m2) patients. Obes Surg 2014;24:1044–1051. 12. Kim Z, Hur KY. Laparoscopic mini-gastric bypass for type 2 diabetes: the preliminary report. World J Surg 2011;35:631–636. 13. Dixon JB, Hur KY, Lee WJ, et al. Gastric bypass in Type 2 diabetes with BMI , 30: weight and weight loss have a major influence on outcomes. Diabet Med 2013;30:e127–e134. 14. Wilkinson CP, Ferris FL III, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003;110: 1677–1682. 15. Heneghan HM, Cetin D, Navaneethan SD, et al. Effects of bariatric surgery on diabetic nephropathy after 5 years of follow-up. Surg Obes Relat Dis 2013;9:7–14. 16. Thomas RL, Prior SL, Barry JD, et al. Does bariatric surgery adversely impact on diabetic retinopathy in persons with
17.
18.
19.
20.
21.
22. 23.
24.
25. 26.
27.
28.
29.
30.
943
morbid obesity and type 2 diabetes? A pilot study. J Diabetes Complications 2014;28:191–195. Varadhan L, Humphreys T, Walker AB, et al. Bariatric surgery and diabetic retinopathy: a pilot analysis. Obes Surg 2012;22: 515–516. Thaler JP, Cummings DE. Minireview: hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. Endocrinology 2009;150:2518–2525. Chantelau E. Evidence that upregulation of serum IGF-1 concentration can trigger acceleration of diabetic retinopathy. Br J Ophthalmol 1998;82:725–730. Zhong Y, Wang JJ, Zhang SX. Intermittent but not constant high glucose induces ER stress and inflammation in human retinal pericytes. Adv Exp Med Biol 2012;723:285–292. Silva RA, Morton JM, Moshfeghi DM. Severe worsening of diabetic retinopathy following bariatric surgery. Ophthalmic Surg Lasers Imaging Retina 2013;44:e11–e14. American Diabetes Association.Diabetic nephropathy. Diabetes Care 2000;23:S69–S72. Vigstrup J, Mogensen CE. Proliferative diabetic retinopathy: at risk patients identified by early detection of microalbuminuria. Acta Ophthalmol (Copenh) 1985;63:530–534. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012;366:1577–1585. Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. Med Clin North Am 2004;88:1001–1036. Heilig CW, Concepcion LA, Riser BL, et al. Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J Clin Invest 1995;96:1802–1814. Fioretto P, Steffes MW, Brown DM, Mauer SM. An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. Am J Kidney Dis 1992;20:549–558. Vora JP, Dolben J, Dean JD, et al. Renal hemodynamics in newly presenting non-insulin dependent diabetes mellitus. Kidney Int 1992;41:829–835. Heng LZ, Comyn O, Peto T, et al. Diabetic retinopathy: pathogenesis, clinical grading, management and future development. Diabet Med 2013;30:640–650. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal diseases. N Engl J Med 1994;331: 1480–1487.
D
achieved glycemic control in significantly more patients than intensive medical therapy alone. In this randomized controlled trial, remission of diabetes, which was defined as a glycated hemoglobin level #6.0% without medication, occurred in 21 of 50 patients (42%) 12 months after gastric bypass surgery.7 Glycated hemoglobin levels were decreased markedly at 3 months postoperatively. This rapid improvement is the main advantage of bariatric surgery. Several studies have reported that a rapid change in glycemic control can result in a paradoxical deterioration of DR.9,10 Although the glycated hemoglobin level was improved, more than half of the patients required oral hypoglycemic agents after bariatric surgery. Therefore, rapid progression of DR might occur in patients who undergo bariatric surgery. However, the remission of diabetes is a novel clinical situation in T2DM treatment.7,8 The clinical course of DR after
iabetic retinopathy (DR) is the leading cause of legal blindness in developed countries.1,2 In Type 2 diabetes (T2DM), .25% of patients develop DR within 2 years of diagnosis.3 Intensive medical therapy can delay the progression of DR, but only about a half of patients achieve sufficient glycemic control.4–6 Bariatric surgery has been performed widely as a metabolic surgery to treat poorly controlled diabetes.7,8 The Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial showed that bariatric surgery plus medical therapy From the Departments of *Ophthalmology, and †Surgery, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea. Supported by the Soonchunhyang University Research Fund. None of the authors have any conflicting interests to disclose. Reprint requests: Kyung Seek Choi, MD, Department of Ophthalmology, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, 59, Daesagwan-ro, Yongsan-gu, Seoul 140-743, Korea; e-mail: [email protected]
935
936
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 5
remission of diabetes is seldom reported. Considering the growing number of patients who have undergone bariatric surgery, this should be addressed. Therefore, the aim of this retrospective study primarily was to evaluate the clinical course of DR in patients with T2DM who underwent bariatric surgery. Risk factors associated with the progression of DR were also analyzed. Methods Consecutive patients who underwent bariatric surgery for T2DM treatment between September 2009 and March 2013 were enrolled. The medical records of the patients who met the following inclusion criteria were reviewed retrospectively: 1) preoperative evaluation within 3 months before bariatric surgery; 2) postoperative follow-up for at least 12 months; and 3) the absence of retinal vascular disease except DR. The research adhered to the tenets of the Declaration of Helsinki. The institutional review board/ethics committee approval was obtained for this retrospective study, and informed consent was obtained from all participants before bariatric surgery. Bariatric Surgery All patients underwent laparoscopic singleanastomosis gastric bypass with the five-trocar method performed by a single experienced team (M.J.K. and K.Y.H.). The details of the surgical procedure have been described elsewhere.11 The antidiabetic effect of laparoscopic single-anastomosis gastric bypass in Korean patients with T2DM was also reported previously.11–13 Ophthalmic Examinations All patients underwent an ophthalmic examination preoperatively, which included the corrected distance visual acuity, slit-lamp biomicroscopy, tonometry, fundus photography, and a dilated fundus examination. The same ophthalmic examinations were performed at every 3 months postoperatively. All ophthalmic examinations were performed by two experienced retinal specialists (S.J.L. and K.S.C.). Based on the physician’s decision, optical coherence tomography and fluorescein angiography (Spectralis HRA + optical coherence tomography; Heidelberg Engineering, Dossenheim, Germany) were performed to evaluate the severity of DR.
and laboratory values. We also assessed the body mass index (BMI), glycated hemoglobin and fasting glucose levels, cholesterol profile, and renal function profile at baseline and every 3 months postoperatively. Outcome Measures The main outcome measure was the clinical course of DR after bariatric surgery. Diabetic retinopathy severity was classified based on the clinical records, fundus color photographs, optical coherence tomography, and fluorescein angiography according to the international clinical DR and diabetic macular edema severity scale proposed by the Global Diabetic Retinopathy Project Group.14 Progression of DR was defined as either 1) an increase in severity or 2) the development of vitreous hemorrhage or diabetic macular edema requiring intervention. Secondary outcome measures were corrected distance visual acuity, intraocular pressure, BMI, laboratory data, and changes in medications. The T2DM remission rate was also assessed. Remission of diabetes was defined as the maintenance of a glycated hemoglobin level #6.0% without oral hypoglycemic agents or insulin after surgery.7 The latest laboratory results were used as the postoperative values in the statistical analysis. The Study Groups The patients were divided into two groups: the progression group consisted of patients with DR progression after bariatric surgery and the nonprogression group comprised of patients with no DR progression. Statistical Analysis All statistical analyses were performed with SPSS version 19.0 (SPSS, an IBM company, Chicago, IL). Preoperative and postoperative values for the same group were compared with Wilcoxon’s signed-rank test. The Mann–Whitney U test and Fisher’s exact test were used to compare the two groups. Binomial logistic regression analysis was performed to identify factors associated with the progression of DR. The odds ratio of the factors detected in the univariate analysis and their 95% confidence intervals were calculated. A value of P , 0.05 was considered to indicate statistical significance. Results
Other Data Collections and Assessment
Study Population
At baseline, we collected data on demographic information, coexisting diseases, use of medications,
Twenty-eight patients underwent bariatric surgery and eligible preoperative evaluation. One patient (no
CHANGES IN DR AFTER BARIATRIC SURGERY KIM ET AL
937
Three of 6 patients were in the nonprogression group and had no DR preoperatively and postoperatively. The other three were in the progression group. These patients entered remission of T2DM within 6 months after surgery, and DR progressed after the remission of T2DM (Table 2; Patients 2, 8, and 9).
DR preoperatively) had branch retinal vein occlusion, and seven patients received postoperative follow-up in local hospitals. Of these patients, three had no DR, two had mild nonproliferative DR (NPDR), one had severe NPDR, and one had proliferative DR preoperatively. These 8 patients were therefore excluded, whereas the remaining 20 patients met the inclusion criteria and were included in the analysis. Of the 20 patients, 9 patients (45%) had DR progression after bariatric surgery and were divided into progression group. Eleven patients (55%) were in the nonprogression group. The median follow-up duration was 28.0 months (interquartile range [IQR], 13.5–42.5 months) in the progression group and 26.0 months (IQR, 13.0– 36.0 months) in the nonprogression group (P = 0.84). The details of demographic characteristics of patients before bariatric surgery are presented in Table 1.
Changes in Other Clinical Data After Bariatric Surgery All patients (40 eyes) had a corrected distance visual acuity of 20/40 or better before bariatric surgery. No patient in the nonprogression group had visual loss during the follow-up period. In the progression group, seven patients had a visual loss of 3 or more Snellen lines (Patients 2–8). Only Patient 3, who had proliferative DR before surgery, developed neovascular glaucoma in the right eye postoperatively. Despite Ahmed glaucoma valve implantation, this patient subsequently developed legal blindness. Except for the right eye of Patient 3, none of the eyes had a high intraocular pressure preoperatively or postoperatively. Of overall 20 patients, none of the patients had uncontrolled hypertension (HTN). The median postoperative BMI, glycated hemoglobin level, and fasting glucose level were 22.5 kg/m2 (IQR, 21.1– 23.6 kg/m2), 7.0% (IQR, 5.9–7.8%), and 112.0 mg/dL (IQR 104.5–132.0 mg/dL) in the progression group, and 23.4 kg/m2 (IQR, 21.6–24.1 kg/m2), 6.7% (IQR, 5.6–9.4%), and 131.0 mg/dL (IQR 109.0– 179.0 mg/dL) in the nonprogression group, respectively. These values were significantly lower than the preoperative values (P , 0.01 for all). The median postoperative serum total cholesterol level and creatinine level were 168.0 mg/dL (IQR, 148.0–206.5 mg/dL) and 0.86 mg/dL (IQR, 0.72– 1.15 mg/dL) in the progression group, and 164.0 mg/dL (IQR, 152.0–199.0 mg/dL) and 0.60 mg/dL (IQR, 0.54–0.66 mg/dL) in the nonprogression group, respectively. The differences were not
Clinical Course of Diabetic Retinopathy After Bariatric Surgery In the nonprogression group, 10 patients had no DR before surgery and only 1 patient had preexisting mild NPDR. Diabetic retinopathy regression was not observed in any patient during the study period. In the progression group, two patients had no DR before surgery and seven patients had preexisting DR. Three patients had mild NPDR, two had moderate NPDR, and further three patients had severe NPDR or proliferative DR. Among them, five patients underwent progression of DR requiring intervention. The preoperative and postoperative severities of DR in the progression group are shown in Table 2. Representative clinical cases are presented in Figures 1 and 2. Diabetic Retinopathy in Remitted Diabetes After Bariatric Surgery Six (30%) entered remission of T2DM postoperatively and maintained a glycated hemoglobin level #6.0% without oral hypoglycemic agents or insulin.
Table 1. Demographic Characteristics of Study Population Before the Bariatric Surgery Total (N = 20) Age (years) Female, n (%) BMI (kg/m2) Duration of DM (years) Hypertension, n (%) Medication, n (%) OHA only Insulin ± OHA
50.5 14 25.4 10.0 7
(37.5–57.0) (70) (22.4–28.2) (5.0–14.8) (35)
15 (75) 5 (25)
Values are median (IQR) or N (%). Mann–Whitney U test or Fisher’s exact test. DM, diabetes mellitus; OHA, oral hypoglycemic agent.
Progression (N = 9) 53.0 5 24.5 10.0 5
(38.0–61.0) (55.6) (21.1–28.1) (7.5–22.0) (55.6)
6 (66.7) 3 (33.3)
Nonprogression (N = 11) 44.0 9 25.9 5.0 2
(37.0–53.0) (81.8) (23.2–28.5) (4.0–10.0) (18.2)
9 (81.8) 2 (18.2)
P 0.295 0.336 0.456 0.067 0.160 0.617
Preoperative Data
1
2
3
4
61
42
61
53
F
F
M
M
DM Duration (years) 10
10
20
20
Preoperative HTN Medication +
−
+
−
OHA
OHA
OHA + I
OHA
BMI (kg/ m2)
HbA1c (%)
28.2
11.3
24.0
20.1
22.1
8.8
7.8
9.3
AU (mg/ day)
BMI (kg/ m2)
HbA1c (%)
132.2
22.0
7.0
88.9
44.5
39.6
20.3
23.0
21.8
5.7
6.5
7.3
AU (mg/ day) 122.3
412.1
25.3
38.8
Severity of DR
Eye R
Mild NPDR
L
Mild NPDR
R
No DR
L
No DR
R
PDR, s/p PRP
L
PDR, s/p PRP
R
R L R L R
Moderate NPDR Moderate NPDR PDR, s/p PRP PDR, s/p PRP Severe NPDR Severe NPDR Mild NPDR
L
Mild NPDR
R
R
Moderate NPDR Moderate NPDR No DR
L
No DR
L 5
57
F
5
−
I
19.4
12.9
2,314.0
19.8
8.0
2,315.0
6
30
F
10
+
OHA
25.4
7.6
15.3
22.5
7.3
15.1
7
51
F
24
+
OHA
26.0
9.4
1,419.9
24.1
7.7
0.3
8
63
M
27
+
I
31.1
6.4
5,167.2
22.6
6.0
2,262.7
L 9
34
M
3
−
OHA
28.1
11.1
72.8
24.5
5.8
4.7
Preoperative
Last F/U Moderate NPDR Moderate NPDR Moderate NPDR Moderate NPDR PDR, NVG
Tx None
F/U (months) 46
None None
30
None AGV, implant STTA
PDR, moderate DME PDR, VH PRP PDR
PRP
PDR, VH PDR, VH PDR, VH PDR, VH Severe NPDR Severe NPDR PDR
PRP TPPV IVBI IVBI None
PDR
PRP
Moderate NPDR Moderate NPDR
None
42
43
12 22 28
None PRP
14
13
None
(+), positive; (−), negative; AGV, Ahmed glaucoma valve; AU, albuminuria; DM, diabetes mellitus; DME, diabetic macular edema; F, female; F/U, follow-up duration; HbA1c, glycated hemoglobin; I, insulin; IVBI, intravitreal bevacizumab injection; L, left; M, male; NVG, neovascular glaucoma; OHA, oral hypoglycemic agent; PDR, proliferative diabetic retinopathy; PRP, panretinal photocoagulation; R, right; STTA, sub-Tenon triamcinolone acetonide injection; TPPV, trans pars plana vitrectomy; Tx, treatment; VH, vitreous hemorrhage.
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 5
Age No. (years) Sex
Postoperative Data
938
Table 2. Clinical Courses of Nine Patients Who Underwent Progression of DR After Bariatric Surgery
CHANGES IN DR AFTER BARIATRIC SURGERY KIM ET AL
939
Fig. 1. The clinical course of DR of Patient 6. At the time of surgery, both eyes of the patient had severe NPDR. No evidence of neovascularization was detected with either dilated fundus examination or fluorescein angiography (A and B). Neovascularization and vitreous hemorrhage developed in both eyes 8 months after the bariatric surgery (C and D). Because this young patient did not want to undergo laser therapy, each eye was treated with a single intravitreal injection of bevacizumab. No significant vitreous hemorrhage or diabetic macular edema occurred over the next 12 months.
significant compared with the preoperative values (Table 3). All patients in both groups revealed the normal serum creatinine level preoperatively and postoperatively. Eight of the nine patients in the progression group had albuminuria before surgery. The urinary albumin level improved in six patients in the progression group. The number of patients with albuminuria decreased from eight to five without any developing new albuminuria in the progression group. Three of 11 patients in the nonprogression group had microalbuminuria (30–300 mg/day) before surgery. None of the patients in the nonprogression group had albuminuria postoperatively.
progression. Age, coexisting HTN, the use of insulin, BMI, glycated hemoglobin level, total cholesterol level before bariatric surgery, and remission of T2DM were not associated with the progression of DR in the univariate analyses. The duration of T2DM increased the odds of DR progression with borderline significance (P = 0.05) but was not significant in the multivariate analysis (P = 0.16). Preexisting DR and albuminuria were identified as significant risk factors in both univariate and multivariate analyses. The detailed results of the univariate logistic regression of each factor are presented in Table 3.
Discussion Factors Associated With Progression of Diabetic Retinopathy The odds ratio and 95% confidence intervals were used to identify the factors associated with DR
Observational studies have suggested that bariatric surgery can improve or halt the development of microvascular complications such as diabetic nephropathy and retinopathy.15–17 Suggested weight-dependent
940
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 5
Fig. 2. The clinical course of DR of Patient 9. A 34-year-old man with uncontrolled diabetes had taken an oral hypoglycemic agent for 3 years preoperatively. He had an HbA1c of 11.1% and microalbuminuria, but no evidence of DR was detected by dilated fundus examination at the time of surgery (A and B). Remission of diabetes was evident based on the HbA1c level and oral glucose tolerance test 3 months postoperatively. Remission of microalbuminuria also occurred within 6 months. However, NPDR developed and progressed rapidly to moderate NPDR (C–F) 9 months after surgery.
and weight-independent mechanisms underlying the antidiabetic impact of bariatric surgery included 1) enhanced nutrient stimulation of lower intestinal hormones (e.g., glucagon-like Peptide 1); 2) altered physiology by excluding ingested nutrients from the upper intestine, compromised ghrelin secretion; 3) the modulation of intestinal nutrient sensing and regulation of insulin sensitivity; and 4) other changes not yet characterized fully.18 A marked improvement in
the index for homeostasis model assessment of insulin resistance, which might be linked to be the attenuation of chronic inflammation, has been reported after bariatric surgery.7 Bariatric surgery can lead to a rapid significant improvement in glycemic control in T2DM. Although intense glycemic control can delay the onset and progression of DR, a rapid change in glycemic control might also result in the paradoxical progression of
CHANGES IN DR AFTER BARIATRIC SURGERY KIM ET AL
941
Table 3. Factors Associated With Progression of DR After the Bariatric Surgery Factors Age (years) DM duration (years) Coexisting HTN, n (%) Insulin ± OHA Preexisting DR Albuminuria ($30 mg/day) BMI (kg/m2) Glycated hemoglobin (%) Fasting glucose (mg/dL) Total cholesterol (mg/dL) DM remission after surgery, n (%)
Progression (N = 9) 53.0 10.0 5 5 7 8 24.5 9.3 184.0 199.0 3
(38.0–61.0) (7.5–22.0) (55.6) (55.6) (77.8) (88.9) (21.1–28.2) (7.7–11.2) (145.5–279.0) (168.0–249.0) (33.3)
Nonprogression (N = 11) 44.0 5.0 2 3 1 3 25.9 9.5 211.0 174.0 3
(37.0–53.0) (4.0–10.0) (18.2) (27.3) (9.1) (27.3) (23.2–28.5) (8.3–10.5) (173.0–258.0) (138.0–199.0) (27.3)
OR
95% CI
P
1.0 1.2 5.6 2.3 31.5 21.3 0.9 0.9 1.0 1.0 1.3
0.962–1.123 0.998–1.412 0.747–42.359 0.285–17.759 2.350–422.299 1.811–251.264 0.715–1.141 0.579–1.472 0.985–1.014 0.993–1.028 0.196–9.083
0.333 0.052 0.160 0.617 0.005* 0.010* 0.393 0.737 0.898 0.250 1.000
Values are median (IQR) or N (%). *P , 0.05; univariate logistic regression. CI, confidence interval; DM, diabetes mellitus; OHA, oral hypoglycemic agent; OR, odds ratio.
DR.9,10 One possible mechanism of the paradoxical progression is an insulin-like growth factor 1 (IGF1)-induced cascade of intracellular signaling.16 The serum IGF-1 level is negatively correlated with the glucose level. A rapid improvement in glycemic control up-regulates the serum level of IGF-1, a potent angiogenic and mitogenic hormone.19 If the retina is damaged sufficiently through hypoxia, the upregulated IGF-1 might promote the progression of DR. The induction of endoplasmic reticulum stress through the shift from high to low normal glucose was also postulated as a mechanism of the paradoxical progression.16 This can result in the inflammation of retinal pericytes and deteriorate the autoregulation of the retinal circulation.20 A few studies have reported the changes in DR after bariatric surgery. Varadhan et al17 reported the changes in 23 patients: 2 (9%) developed new DR, whereas 2 others (9%) had progression of preexisting DR. They also reported the postoperative regression of DR in 2 patients (9%). Thomas et al16 assessed the changes in DR in 38 patients after the bariatric surgery and reported that 26 (68.4%) had no change in DR status, 5 (13.2%) had apparent regression of DR, and 7 (18.4%) had progression of DR. Of the 7 patients who had DR progression, 4 patients with no DR preoperatively developed only 1 or 2 microaneurysms; 1 patient with 7 microaneurysms and 1 blot hemorrhage before surgery had .20 microaneurysms and 8 blot hemorrhages postoperatively; another patient with small venous loops and intraretinal microvascular abnormalities before surgery had additional hard exudates at the fovea; and the last patient with exudative maculopathy had additional microaneurysms and hemorrhage postoperatively. However, previous studies have critical shortcomings. These studies used only standardized digital photographs to assess the severity
of DR without a dilated fundus examination. The severity of DR cannot be assessed precisely with the status of the posterior pole, and the disappearance of one or two microaneurysms at the posterior pole does not indicate the regression of DR. Furthermore, Thomas et al16 assessed the DR progression using self-proposed severity scales, which are not used widely in ophthalmology. Silva et al21 reported the case of a white female who suffered rapid worsening DR within 1 month of the bariatric surgery. This patient had very severe NPDR preoperatively. The glycated hemoglobin level decreased from 8.8% to 7.2%, but she underwent diabetic vitrectomy because of a vitreous hemorrhage and tractional retinal detachment at 3.5 months after the bariatric surgery. In this study, we assessed primarily the severity of DR and progression of DR according to the disease severity scale proposed by the Global Diabetic Retinopathy Project Group.14 No patient revealed regression of DR. Two patients with mild NPDR preoperatively progressed to moderate NPDR. All five patients with moderate or more severe NPDR preoperatively had progression that required intervention (Table 2). Preexisting DR and albuminuria were identified as factors significantly associated with DR progression. We think that these findings in the patients with moderate or more severe NPDR were related to the up-regulation of IGF-1 after bariatric surgery. Two patients with no previous DR developed moderate NPDR 30 months and 13 months postoperatively, respectively. Both of them had microalbuminuria preoperatively, which suggests that subclinical diabetic changes might have occurred in their retinas before the bariatric surgery.22,23 The proportion and severity of DR progression in this study were greater and more severe than reported previously.16,17 These differences might be explained
942
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 5
by several factors. First, the follow-up period was longer in our study. Second, the higher glycated hemoglobin level (9.6%) before surgery might have contributed to the results (8.2 and 7.9% in the 2 previous studies). However, the preoperative glycated hemoglobin level did not show a significant association with DR progression in our or another study.16 Third, the characteristics of Korean T2DM patients might explain the differences: they have weaker pancreatic islet cells and are more susceptible to insulin resistance than other ethnic groups.11 They also have a lower mean BMI, which might weaken the weightdependent antidiabetic effect of the surgery.12 However, the preoperative BMI was not associated with disease progression or glycemic control in this study and other randomized controlled trials.24 We also assessed the changes in DR in patients who entered remission of T2DM. The postoperative T2DM remission rate was 30% (6 patients) in our series, which was comparable with published reports.7,11,13 Three of the six patients with remission of T2DM had progression of DR, and two of them had no DR preoperatively. Our study showed that the remission of T2DM could not halt the development or progression of DR. Regarding secondary outcome measures, bariatric surgery significantly influenced BMI, glycemic control, and microalbuminuria, but not total cholesterol. These have been identified in several prospective studies with long-term follow-up.8,15 Coexisting HTN did not show a significant association with DR progression in our study. However, the association between blood pressure and DR progression should be reevaluated because no patient had uncontrolled HTN. Unlike DR, none of the 9 patients with no albuminuria before surgery developed microalbuminuria postoperatively, and 9 of the 11 patients with albuminuria benefited from the bariatric surgery in terms of the urine albumin level. The dissociation of the changes in retinopathy and nephropathy after bariatric surgery in patients with T2DM is a novel finding of our study. We speculate that it is related to the difference in the pathogenesis of the two major microvascular complications of diabetes. The key pathophysiologic events in diabetic nephropathy are alteration in the molecular structure of the components of the glomerulus and its basement membrane caused by hyperglycemia-induced glycosylation of tissue protein, and intraglomerular HTN.25–28 Hyperglycemia-induced damage is also important in the development of DR. Hyperglycemia causes apoptosis of retinal capillary pericytes through intracellular cascade signaling, which leads to weakness in the capillary walls, aneurysm formation, fluid leakage, impaired vascular function, and ultimately ischemia
and infarction of the retina.25,29 The damaged retina itself releases vasoproliferative factors, which can induce further retinal damage, including neovascularization independently of hyperglycemia.30 There are several limitations to this study. In Asia, T2DM tends to occur in patients with a relatively lower BMI compared with western countries.12 Our patients had chosen to receive bariatric surgery as a metabolic surgery, rather than for obesity. Therefore, the results may not be directly comparable with western T2DM patients who are in the obese range. The retrospective design and few patients are further limitations. Moreover, 8 of 28 patients were excluded from the analysis. Because there are few medical centers in Korea capable of performing the metabolic surgery during the study period, seven patients were referred to our hospital for the bariatric surgery and received postoperative follow-up in their local hospitals. Therefore, conclusions cannot be drawn from this series regarding the exact rates of DR progression after the bariatric surgery at this time. Nevertheless, there are several strengths of this investigation above and beyond previously published data. First, this is the first study to evaluate the progression of DR after bariatric surgery based on the results of detailed ophthalmic examinations and a general severity scale. Regression of DR was not observed in any patient in this study. Second, the dissociation of the changes in retinopathy and nephropathy is the novel finding of this study, which was not addressed in the previous investigations. Third, we evaluated the risk factors for DR progression and demonstrated that the development and progression of DR can occur even in patients who show remission of diabetes or in patients without previous DR after the bariatric surgery. The result of this pilot study warrants the further prospective investigations involving a greater number of patients. In conclusion, physicians should be aware of possible DR progression after bariatric surgery and should educate their patients about this. All patients with T2DM who undergo the bariatric surgery should have regular follow-up, regardless of the severity of previous DR or remission of diabetes. Key words: bariatric surgery, clinical course, diabetic retinopathy. References 1. Fong DS, Aiello LP, Ferris FL III, Klein R. Diabetic retinopathy. Diabetes Care 2004;27:2540–2553. 2. Zhang X, Saaddine JB, Chou CF, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA 2010;304: 649–656.
CHANGES IN DR AFTER BARIATRIC SURGERY KIM ET AL 3. Fong DS, Aiello L, Gardner TW, et al. Retinopathy in diabetes. Diabetes Care 2004;27:S84–S87. 4. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: 837–853. 5. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977–986. 6. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004;291:335–342. 7. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med 2012;366:1567–1576. 8. Sjostrom L, Lidroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Eng J Med 2004;351:2683–2693. 9. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology 1995;102:647–661. 10. Brooks AM, Lissett CA. A dramatic deterioration in diabetic retinopathy with improvement in glycated hemoglobin (HbA (1c)) on exenatide treatment. Diabet Med 2009;26:190. 11. Kim MJ, Hur KY. Short-term outcomes of laparoscopic single anastomosis gastric bypass (LSAGB) for the treatment of type 2 diabetes in lower BMI (,30 kg/m2) patients. Obes Surg 2014;24:1044–1051. 12. Kim Z, Hur KY. Laparoscopic mini-gastric bypass for type 2 diabetes: the preliminary report. World J Surg 2011;35:631–636. 13. Dixon JB, Hur KY, Lee WJ, et al. Gastric bypass in Type 2 diabetes with BMI , 30: weight and weight loss have a major influence on outcomes. Diabet Med 2013;30:e127–e134. 14. Wilkinson CP, Ferris FL III, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003;110: 1677–1682. 15. Heneghan HM, Cetin D, Navaneethan SD, et al. Effects of bariatric surgery on diabetic nephropathy after 5 years of follow-up. Surg Obes Relat Dis 2013;9:7–14. 16. Thomas RL, Prior SL, Barry JD, et al. Does bariatric surgery adversely impact on diabetic retinopathy in persons with
17.
18.
19.
20.
21.
22. 23.
24.
25. 26.
27.
28.
29.
30.
943
morbid obesity and type 2 diabetes? A pilot study. J Diabetes Complications 2014;28:191–195. Varadhan L, Humphreys T, Walker AB, et al. Bariatric surgery and diabetic retinopathy: a pilot analysis. Obes Surg 2012;22: 515–516. Thaler JP, Cummings DE. Minireview: hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. Endocrinology 2009;150:2518–2525. Chantelau E. Evidence that upregulation of serum IGF-1 concentration can trigger acceleration of diabetic retinopathy. Br J Ophthalmol 1998;82:725–730. Zhong Y, Wang JJ, Zhang SX. Intermittent but not constant high glucose induces ER stress and inflammation in human retinal pericytes. Adv Exp Med Biol 2012;723:285–292. Silva RA, Morton JM, Moshfeghi DM. Severe worsening of diabetic retinopathy following bariatric surgery. Ophthalmic Surg Lasers Imaging Retina 2013;44:e11–e14. American Diabetes Association.Diabetic nephropathy. Diabetes Care 2000;23:S69–S72. Vigstrup J, Mogensen CE. Proliferative diabetic retinopathy: at risk patients identified by early detection of microalbuminuria. Acta Ophthalmol (Copenh) 1985;63:530–534. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012;366:1577–1585. Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. Med Clin North Am 2004;88:1001–1036. Heilig CW, Concepcion LA, Riser BL, et al. Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J Clin Invest 1995;96:1802–1814. Fioretto P, Steffes MW, Brown DM, Mauer SM. An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. Am J Kidney Dis 1992;20:549–558. Vora JP, Dolben J, Dean JD, et al. Renal hemodynamics in newly presenting non-insulin dependent diabetes mellitus. Kidney Int 1992;41:829–835. Heng LZ, Comyn O, Peto T, et al. Diabetic retinopathy: pathogenesis, clinical grading, management and future development. Diabet Med 2013;30:640–650. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal diseases. N Engl J Med 1994;331: 1480–1487.
