lisinopril and Diabetic-Retinopathy

The pathogenesis and medical management of diabetic retinopathy is reviewed. The importance of good control of blood glucose and blood pressure remain key elements in the prevention and treatment of diabetic retinopathy, and a number of specific metabolic pathways have been identified that may be useful additional targets for therapeutic intervention. Trial data, however, aimed specifically to answer the questions of optimum medical management are limited, so the DIRECT study of renin-angiotensin blockade using oral candesartan 32 mg daily is a welcome addition to our knowledge. This arose from the promising improvement of retinopathy outcomes in the EUCLID study of lisinopril in type I diabetes. In DIRECT, 5 years of candesartan treatment in type I diabetes reduced the incidence of retinopathy by two or more steps (EDTRS) in severity by 18% (P=0.0508) and, in a post hoc analysis, reduced the incidence of retinopathy by three-step progression by 35% (P=0.034). In type I diabetes patients there was no effect on progression of established retinopathy. In contrast, in type II diabetes, 5 years of candesartan treatment resulted in 34% regression of retinopathy (P=0.009). Importantly, an overall significant change towards less-severe retinopathy was noted in both type I and II diabetes (P

Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Incidence; Lisinopril; Tetrazoles

Retinopathy is the most common complication of diabetes, and a leading cause of blindness in people of working age. Optimal blood pressure and metabolic control can reduce the risk of diabetic retinopathy, but are difficult to achieve in clinical practice. In the EUCLID Study, the angiotensin converting enzyme (ACE) inhibitor lisinopril reduced the risk of progression of retinopathy by approximately 50%, and also significantly reduced the risk of progression to proliferative retinopathy. These findings are consistent with extensive evidence that the renin-angiotensin system is expressed in the eye, and that adverse effects of angiotensin II on retinal angiogenesis and function can be inhibited by ACE inhibitors or angiotensin II-receptor blockers. However, in the EUCLID Study retinopathy was not a primary end-point and the study was not sufficiently powered for the eye-related outcomes. Hence, the Diabetic Retinopathy Candesartan Trials (DIRECT) programme has been established to determine whether AT(1)-receptor blockade with candesartan can prevent the incidence and progression of diabetic retinopathy. This programme comprises three studies, involving a total of 4500 patients recruited from about 300 centres worldwide. The patients are normotensive or treated hypertensive individuals, and so the DIRECT programme should assess the potential of an AT(1)-receptor blocker to protect against the pathological changes in the eye following diabetes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Humans; Hypertension; Lisinopril; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Retina; Tetrazoles

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetic Retinopathy; Humans; Hypertension; Lisinopril; Randomized Controlled Trials as Topic; Renin-Angiotensin System

Diabetic retinopathy is characterized by morphological changes in the retina secondary to disturbances in retinal blood flow. It has been shown that antihypertensive treatment has a protective effect on the development of diabetic retinopathy, and evidence suggests that inhibitors of the renin-angiotensin system have a protective effect beyond the antihypertensive effect. The background for this additional effect is unknown but might be related to an effect on retinal autoregulation.. In a double-blinded, two-way cross-over study, 25 normotensive patients with type 1 diabetes (T1D) aged 20.6-33.9 (mean 27.9) with mild retinopathy were randomized to receive either 5 mg of the calcium channel blocker (CCB) amlodipine for 14 days followed by a washout period and treatment with 10 mg of the angiotensin converting enzyme (ACE) inhibitor lisinopril for another 14 days or the two treatments in the reverse order. Using a Dynamic Vessel Analyzer (DVA), the diameter response of retinal arterioles during an acute increase in the blood pressure induced by isometric exercise, during flicker stimulation and during both stimulus conditions simultaneously was studied before and during the two treatments periods.. Amlodipine and lisinopril induced a similar non-significant decrease in the arterial blood pressure. At baseline, the arterial diameter decreased by 2.4 ± 0.9% (p = 0.004) during isometric exercise, increased by 2.2 ± 0.9% (p = 0.019) during flicker stimulation and increased by 1.8 ± 0.9% (p = 0.03) during the combined stimulus conditions. Neither of the antihypertensive drugs amlodipine (p = 0.76) or lisinopril (p = 0.11) changed the diameter response of retinal vessels significantly; however, the two treatments induced a different response in the veins during combined exercise and flicker (p = 0.021).. Short-term treatment with amlodipine and lisinopril had no significant effect on retinal autoregulation in young normotensive patients with T1D and mild retinopathy, and this lack of effect was similar for the two drugs. A possible normalizing effect of antihypertensive treatment on retinal autoregulation was not observed; however, it might take longer time to improve autoregulation than to reduce the arterial blood pressure.

Topics: Adult; Amlodipine; Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Double-Blind Method; Exercise; Female; Homeostasis; Humans; Intraocular Pressure; Lisinopril; Male; Retinal Artery; Tonometry, Ocular; Young Adult

The effect of lisinopril (an angiotensin-converting enzyme inhibitor) on diabetic macular edema (DME) was investigated by quantitative measurement of macular thickness. In a nonrandomized clinical trial, 19 normotensive type 2 diabetic patients with DME prospectively received oral lisinopril therapy for 2 months. Another 10 normotensive type 2 diabetic patients with similar DME were prospectively followed for two months without treatment. Central macular thickness was measured with a retinal thickness analyzer (RTA). In the lisinopril group, visual acuity improved by two lines or more in two out of 19 eyes (11%), was unchanged in 15 eyes (78%), and deteriorated by two lines or more in two eyes (11%). The mean central macular thickness was significantly reduced after 2 months of treatment (381.3 +/- 121.1 microm) compared with that before administration (475.2 +/- 171.0 microm, P = 0.0093). In the control group, central macular thickness was not significantly decreased after 2 months (458.5 +/- 113.7 microm, P = 0.2178) compared with the baseline value (464.7 +/- 152.2). Fluorescein angiography showed that macular leakage was decreased in 10 patients from the lisinopril group (53%) and was unchanged in nine patients (47%). There was a significant difference of central macular thickness between the patients with and without improvement of macular leakage (P = 0.0040). Lisinopril therapy may reduce macular thickness in patients with DME, as shown by this quantitative study. In addition, quantitative measurement of retinal thickness is useful when evaluating therapeutic agents for DME.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Diabetic Retinopathy; Diagnosis, Computer-Assisted; Diagnostic Techniques, Ophthalmological; Female; Fluorescein Angiography; Humans; Lasers; Lisinopril; Macular Edema; Male; Middle Aged; Retina; Treatment Outcome

Amadori-albumin, a major glycated protein, is involved in experimental hyperglycaemia-induced microvascular complications, and is associated with advanced nephropathy in Type I diabetic patients in humans. Our aim was to assess the association of Amadori-albumin with early nephropathy and with retinopathy in Type I diabetic patients and the involvement of chronic low-degree inflammation therein.. Amadori-albumin, the Amadori product of haemoglobin (HbA1c), C-reactive protein, and fibrinogen levels were measured in the EUCLID study, a 2-year randomised, double-blind, placebo-controlled trial of lisinopril in 447 Type I diabetic patients. Retinal photographs were taken in 341 patients at baseline and 294 at follow up.. Amadori-albumin was positively associated with albumin the excretion rate and retinopathy status (P = 0.0001 and P = 0.02 for trend, respectively) and with the progression from normoalbuminuria to (micro)albuminuria (38.6 U mL(-1) in nonprogressors, 44.3 U mL-1 in progressors; P = 0.02), but not with the development or progression of retinopathy during a 2-year follow up. Amadori-albumin levels at baseline were associated with C-reactive protein and fibrinogen (P = 0.0007 and P = 0.0001, respectively). C-reactive protein and fibrinogen were also associated with albumin excretion rates (P = 0.03 and P = 0.01, respectively) and retinopathy status (P = 0.02 and P = 0.0006, respectively). Adjustment for these inflammatory markers did not markedly attenuate the association between Amadori-albumin and the albumin excretion rate, while adjustment for fibrinogen, but not C-reactive protein, abolished the association between Amadori-albumin and retinopathy. Lisinopril had no impact on the association between the levels of Amadori-albumin and albumin excretion rates or retinopathy.. Amadori-albumin was associated with early nephropathy and with retinopathy in Type I diabetic patients and preceded an increase in albumin excretion rate, but not retinopathy. A chronic low-degree inflammation does not appear to be involved in Amadori-albumin-associated microvascular complications in Type I diabetes.

Topics: Adult; Albumins; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Double-Blind Method; Female; Humans; Lisinopril; Male; Middle Aged; Regression Analysis

To determine whether circulating plasma vascular endothelial growth factor (VEGF) is elevated in the presence of diabetic microvascular complications, and whether the impact of angiotensin-converting enzyme (ACE) inhibitors on these complications can be accounted for by changes in circulating VEGF.. Samples (299/354 of those with retinal photographs) from the EUCLID placebo-controlled clinical trial of the ACE inhibitor lisinopril in mainly normoalbuminuric non-hypertensive Type 1 diabetic patients were used. Albumin excretion rate (AER) was measured 6 monthly. Geometric mean VEGF levels by baseline retinopathy status, change in retinopathy over 2 years, and by treatment with lisinopril were calculated.. No significant correlation was observed between VEGF at baseline and age, diabetes duration, glycaemic control, blood pressure, smoking, fibrinogen and von Willebrand factor. Mean VEGF concentration at baseline was 11.5 (95% confidence interval 6.0--27.9) pg/ml in those without retinopathy, 12.9 (6.0--38.9) pg/ml in those with non-proliferative retinopathy, and 16.1 (8.1--33.5) pg/ml in those with proliferative retinopathy (P = 0.06 for trend). Baseline VEGF was 15.2 pg/ml in those who progressed by at least one level of retinopathy by 2 years compared to 11.8 pg/ml in those who did not (P = 0.3). VEGF levels were not altered by lisinopril treatment. Results were similar for AER.. Circulating plasma VEGF concentration is not strongly correlated with risk factor status or microvascular disease in Type 1 diabetes, nor is it affected by ACE inhibition. Changes in circulating VEGF cannot account for the beneficial effect of ACE inhibition on retinopathy.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Retinopathy; Endothelial Growth Factors; Fibrinogen; Glycated Hemoglobin; Humans; Lisinopril; Lymphokines; Middle Aged; Placebos; Smoking; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; von Willebrand Factor

Retinopathy commonly occurs in people with type 1 diabetes. Strict glycaemic control can decrease development and progression of retinopathy only partially. Blood pressure is also a risk factor for microvascular complications. Antihypertensive therapy, especially with inhibitors of angiotensin-converting enzyme (ACE), can slow progression of nephropathy, but the effects on retinopathy have not been established. We investigated the effect of lisinopril on retinopathy in type 1 diabetes.. As part of a 2-year randomised double-blind placebo-controlled trial, we took retinal photographs at baseline and follow-up (24 months) in patients aged 20-59 in 15 European centres. Patients were not hypertensive, and were normoalbuminuric (85%) or microalbuminuric. Retinopathy was classified from photographs on a five-level scale (none to proliferative).. The proportion of patients with retinopathy at baseline was 65% (117) in the placebo group and 59% (103) in the lisinopril group (p = 0.2). Patients on lisinopril had significantly lower HbA1c at baseline than those on placebo (6.9% vs 7.3 p = 0.05). Retinopathy progressed by at least one level in 21 (13.2%) of 159 patients on lisinopril and 39 (23.4%) of 166 patients on placebo (odds ratio 0.50 [95% CI 0.28-0.89], p = 0.02). This 50% reduction was the same when adjusted for centre and glycaemic control (0.55 [0.30-1.03], p = 0.06). Lisinopril also decreased progression by two or more grades (0.27 [0.07-1.00], p = 0.05), and progression to proliferative retinopathy (0.18 [0.04-0.82], p = 0.03). Progression was not associated with albuminuric status at baseline. Treatment reduced retinopathy incidence (0.69 [0.30-1.59], p = 0.4).. Lisinopril may decrease retinopathy progression in non-hypertensive patients who have type 1 diabetes with little or no nephropathy. These findings need to be confirmed before changes to clinical practice can be advocated.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Humans; Lisinopril; Logistic Models; Male; Risk Factors; Time Factors

We examined whether the renin inhibitor, aliskiren, provides similar or greater protection than ACE inhibition from non-proliferative diabetic retinopathy and from the proliferative neoangiogenesis of oxygen-induced retinopathy.. Transgenic (mRen-2)27 rats, which overexpress mouse renin and angiotensin in extra-renal tissues, were studied. For diabetic studies, non-diabetic, diabetic (streptozotocin, 55 mg/kg), diabetic + aliskiren (10 mg kg(-1) day(-1), pump), or diabetic + lisinopril (10 mg kg(-1) day(-1), drinking water) rats were evaluated over 16 weeks. For oxygen-induced retinopathy studies, rats were exposed to 80% oxygen (22 h/day) from postnatal days 0 to 11, and then room air from postnatal days 12 to 18. Aliskiren (10 or 30 mg kg(-1) day(-1), pump) or lisinopril (10 mg kg(-1) day(-1), drinking water) was administered during retinopathy development between postnatal days 12 and 18.. Systolic BP in diabetic (mRen-2)27 rats was reduced with 10 mg kg(-1) day(-1) aliskiren, but only lisinopril normalised systolic blood pressure. In diabetic (mRen-2)27 rats, 10 mg kg(-1) day(-1) aliskiren and lisinopril reduced retinal acellular capillaries and leucostasis to non-diabetic levels. In oxygen-induced retinopathy, neoangiogenesis and retinal inflammation (leucostasis, ED-1 immunolabelling) were partially reduced by 10 mg kg(-1) day(-1) aliskiren and normalised by 30 mg kg(-1) day(-1) aliskiren, whereas lisinopril normalised neoangiogenesis and reduced leucostasis and ED-1 immunolabelling. Aliskiren and lisinopril normalised retinal vascular endothelial growth factor expression; however, only aliskiren reduced intercellular adhesion molecule-1 to control levels.. Aliskiren provided similar or greater retinal protection than ACE inhibition and may be a potential treatment for diabetic retinopathy.

Topics: Amides; Animals; Animals, Genetically Modified; Diabetic Retinopathy; Female; Fumarates; Lisinopril; Mice; Neovascularization, Pathologic; Oxygen; Rats; Renin

To report the role of retinal hypoxia in development of diabetic macular edema and its management--a new concept.. A 24-year-old diabetic female was seen with bilateral visual blurring for 3 weeks, associated with marked diabetic macular edema, diabetic retinopathy, and non-arteritic anterior ischemic optic neuropathy (NA-AION) in both eyes. She was taking three blood pressure lowering drugs for diabetic neuropathy and nephropathy. Stopping two of those arterial hypotensive drugs, without any of the conventional treatments for diabetic macular edema, resulted in rapid improvement of visual acuity from counting fingers to 20/50 in the right eye, and from 20/80 to 20/25 in the left eye, and complete resolution of macular edema and improvement of retinopathy. Similarly, visual field defects in both eyes improved to almost normal.. The evidence from this diabetic patient suggests that hypoxia caused by fall in perfusion pressure in the retinal capillaries may be playing an important role in the development of diabetic macular edema in some, perhaps many, of these cases.

Topics: Adult; Blood Pressure; Diabetic Nephropathies; Diabetic Retinopathy; Female; Fluorescein Angiography; Follow-Up Studies; gamma-Aminobutyric Acid; Humans; Hypoxia; Insulin; Lisinopril; Macular Edema; Optic Neuropathy, Ischemic; Pregabalin; Proteinuria; Retinal Diseases; Tomography, Optical Coherence; Tramadol; Vision Disorders; Visual Acuity; Visual Field Tests; Visual Fields

Topics: Blood Pressure; Diabetic Retinopathy; Fluorescein Angiography; gamma-Aminobutyric Acid; Humans; Hypoxia; Insulin; Lisinopril; Macular Edema; Optic Neuropathy, Ischemic; Pregabalin; Proteinuria; Retinal Diseases; Retinal Vein Occlusion; Tomography, Optical Coherence; Tramadol; Vision Disorders; Visual Acuity; Visual Fields

Neovascularization in the retina and iris of diabetic patients is a major cause of severe visual loss. However, study of these lesions is compromised by the lack of a comparable diabetic rodent model. Because the vasoactive and angiogenic agent, angiotensin II, is involved in diabetic microvascular disease, we aimed to determine whether endothelial cell proliferation could be induced in the retinae and irides of hypertensive transgenic (mRen-2)27 rats that display an enhanced extra-renal renin-angiotensin system (RAS), including the eye. Six-week-old Ren-2, spontaneously hypertensive, and Sprague-Dawley rats received either streptozotocin or control vehicle and were studied for 36 weeks. Additional nondiabetic and diabetic Ren-2 rats were treated throughout with the angiotensin-converting enzyme inhibitor lisinopril (LIS) (10 mg/kg/day in drinking water). Endothelial cell proliferation was only observed in retinae and irides of diabetic Ren-2 rats and was reduced with LIS. In diabetic Ren-2, vascular endothelial growth factor (VEGF) and VEGFR-2 mRNA were increased in retinae and irides and reduced with LIS. Diabetes activated ocular renin in Ren-2 but not Sprague-Dawley rats. The diabetic Ren-2 rat is a model of intraocular endothelial cell proliferation that can be attenuated by RAS blockade via VEGF-dependent pathways. RAS blockade is a potential treatment for vision-threatening diabetic microvascular complications.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Chronic Disease; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Disease Models, Animal; Endothelial Growth Factors; Endothelium, Vascular; Eye; Female; Heterozygote; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Iris; Lisinopril; Lymphokines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Retina; RNA, Messenger; Streptozocin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

Clinical studies have detected an unexpected inhibition of diabetic retinopathy by angiotensin-converting enzyme (ACE) inhibitors, but the mechanism for this action is unclear. In light of evidence indicating that the severity of hyperglycemia is a major initiating factor in the pathogenesis of the retinopathy, this study was conducted to examine the effect of ACE inhibitors on glucose accumulation in retinas of diabetic rats.. Rats were made experimentally diabetic by injection of streptozotocin and treated with captopril (25 mg/kg body weight per day) or atenolol (10 mg/kg body weight per day) for 8 weeks. Bovine retinal endothelial cells were cultured in medium containing either 5.5 or 25 mM glucose and treated with different concentrations of captopril or lisinopril for 5 days. Glucose content in retinas and cultured cells was measured by spectrometry. Expression of glucose transporter (GLUT)-1 in retinas and cultured cells was determined by Western blot analysis. Glucose uptake was performed by using 3-O-methyl-D-[(3)H] glucose.. Treatment of rats with captopril inhibited the diabetes-induced accumulation of glucose in the retina by 48% (P < 0.01) compared with the diabetic control, but atenolol had no significant effect. Similarly, captopril and lisinopril significantly inhibited intracellular accumulation of glucose in primary bovine retinal endothelial cells cultured in an elevated glucose concentration. These data indicate that the captopril-induced inhibition of glucose accumulation observed in retinal tissue of diabetic rats was not due to reduction in blood pressure or in vascular permeability. Although it had no effect on the expression of the GLUT1 in retinas and cultured retinal endothelial cells, captopril at a concentration of 2 mM significantly inhibited the high-glucose-induced increase in GLUT1-mediated glucose transport in cultured retinal endothelial cells by 67% +/- 10%.. Inhibition of glucose accumulation within retinal cells probably contributes at least in part to the observed inhibition of diabetic retinopathy by ACE inhibitors.

Topics: Adrenergic beta-Antagonists; Aldehyde Reductase; Angiotensin-Converting Enzyme Inhibitors; Animals; Atenolol; Blood Glucose; Blotting, Western; Captopril; Cattle; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Endothelium, Vascular; Glucose; Glucose Transporter Type 1; Lisinopril; Male; Monosaccharide Transport Proteins; Rats; Rats, Sprague-Dawley; Retina; Retinal Vessels

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Glycated Hemoglobin; Humans; Lisinopril; Research Design

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Endothelial Growth Factors; Humans; Lisinopril; Lymphokines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors