Diabetic Microvascular Disease: An Endocrine Society Scientific Statement

Eugene J. Barrett; Zhenqi Liu; Mogher Khamaisi; George L. King; Ronald Klein; Barbara E. K. Klein; Timothy M. Hughes; Suzanne Craft; Barry I. Freedman; Donald W. Bowden; Aaron I. Vinik; Carolina M. Casellini

Disclosures

J Clin Endocrinol Metab. 2017;102(12):4343-4410. 

In This Article

Retinal Microvascular Disease

Introduction

DR and DN are considered the quintessential microvascular complications of diabetes. These complications are frequent and may result in severe visual impairment and renal failure and are associated with poor QOL. Plasma glucose and HgA1c concentration thresholds for the diagnosis of diabetes have been established based upon the correlation of these chemical indices to microvascular changes in the retina, as observed on fundus photography. We review in this study the natural history, pathogenesis, and epidemiology of DR development and progression. We also review the impact of risk factors and comorbidities on DR development and progression and briefly discuss clinical management.

Natural History of DR

We know that a number of subclinical changes in the physiology of the retinal vessels (retinal microaneurysms and blot hemorrhages that can be detected by ophthalmoscopy) occur in persons with diabetes prior to the appearance of the first clinical signs.[175] These changes include disruption of the blood-retinal barrier and increased RBF, most likely due to disturbances in autoregulation. Clinicians do not routinely measure this. Another early change is widening of the retinal venules. One study (in the absence of any other clinical signs of DR) associated a widening of the retinal venules by 10 μm over a 4-year period, with a 26% increase in the risk of incident DR over the next 6 years.[175] These data suggest that measuring venular diameter may provide an even earlier clinically measurable stage of DR than retinal microaneurysms and blot hemorrhages.

Retinal microaneurysms are small outpouchings of the retinal capillaries. Retinal blot hemorrhages often follow but may appear prior to microaneurysms. Both lesions are not pathognomonic of diabetes, as they may appear in 2% to 11% of persons aged 40 years or older without diabetes and are often associated with hypertension.[176]

After the appearance of retinal microaneurysms and/or blot hemorrhages, retinopathy may progress with the appearance of other nonproliferative retinal abnormalities, such as retinal hard exudates (lipid deposits in the retina resulting from lipoprotein leakage from the retinal microvasculature), cotton wool spots [small localized infarctions of the nerve fiber layer of the retina (also called soft exudates)], intraretinal microvascular abnormalities (collateral dilated capillary channels in areas of retinal ischemia), and venous beading (irregular dilation of retinal veins associated with significant retinal ischemia). Retinopathy may further progress to the proliferative stage, characterized by the development of new retinal blood vessels and fibrous tissue at the optic disc or near venules elsewhere in the retina. These new retinal blood vessels may bleed, resulting in preretinal and vitreous hemorrhage, and the fibrovascular tissue can cause traction on the macula, resulting in loss of vision. Although the progression of proliferative disease in untreated eyes is the usual course, spontaneous regression of the new retinal vessels may occur at any stage. Macular edema (thickening of the retina in the macular area) may also develop and regress without treatment. Although clinicians can identify the source and extent of the leakage in the macula by fluorescein angiography, they now usually confirm the retinal thickness and response to treatment in eyes with macular edema by spectral domain optical coherence tomography.[177] Visual loss may result from macular edema or proliferative retinopathy.

Although retinopathy is believed to result from the effects of hyperglycemia, hypertension, and high lipid levels on the retinal microvasculature (see the section on epidemiology), there is also growing evidence of concurrent early neurodegenerative changes of the retinal neuronal cells (e.g., retinal ganglion and Mueller cells, cones), which (in whole) we generally refer to as the neurovascular unit.[178] The neurodegenerative changes are associated with impaired control of the metabolism of neurotransmitter glutamate, apoptosis in the ganglion cells and inner nuclear layer cells, and the activation of microglial cells, resulting in localized inflammation.[178–180] These neuronal changes result in a loss of synaptic activity and loss of dendrites. Levels of brain-derived neurotrophic factor are also reduced.[181,182] Researchers have postulated that these neuronal changes contribute to the development of retinopathy by impairing autoregulation and vascular integrity in persons with T2DM.[183,184] Retinal flicker responses (a neurologic function) are impaired before the onset of retinopathy in people with T1DM.[183,185] Neuropathy may involve nerves in the cornea and pupil in addition to the retinal neuron. Retinal neurodegenerative changes may manifest clinically as a decreased ability to discriminate blue from yellow color, decreases in dark adaptation with decreases in the electroretinograph a-wave and b-wave amplitudes, changes in the oscillatory potentials generated by inner retinal neurons, and changes in contrast sensitivity.[186] We have a poor understanding of the temporal and causative relationships between the neuropathic and retinopathic changes.

Pathogenesis

The pathogenesis of DR is complex (see Biochemical Pathways of Microvascular Injury). A number of possible mechanisms appear to contribute[157,178,187,188] (Figure 3). Hyperglycemia is an important initiator of the disease process. Studies have shown that hyperglycemia induces biochemical, physiological, rheological, hormonal, and other changes that are involved in the pathogenesis of DR (Figure 3). These abnormalities are associated with the development of a number of anatomic changes in the diabetic retina, which include pericyte loss, endothelial cell abnormalities, acellular capillaries, increased BM thickness, and retinal pigment epithelial abnormalities.

Figure 3.

Conceptual diagram showing the effect of hyperglycemia on different mechanisms hypothesized to be involved in the pathogenesis of diabetic retinopathy.

It is likely that the initiation and progression of DR are due to a complex relationship among a number of these factors and pathways, which vary at different stages in the natural history of DR and also vary from individual to individual.

Epidemiology

Prevalence. Epidemiologic population-based studies have provided important descriptive information on the prevalence, incidence, and progression of DR, as well as information on modifiable and potentially intervenable risk factors, such as glycosylated hemoglobin, BP, and lipid levels. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) provided data on the prevalence and severity of DR by duration of diabetes (Figure 4) and the 4-year incidence and progression of DR by age, sex, and duration of diabetes in younger-onset persons with T1DM and older-onset persons with T2DM.[189–192] In the WESDR, the prevalence of DR in patients with T1DM was 17% in those with <5 years of diabetes vs 98% in those with 15 or more years of diabetes; proliferative retinopathy was absent in those with a shorter duration of diabetes, but present in 48% in those with 15 or more years of diabetes. For persons with older-onset T2DMfor <5 years vs 15 or more years, the prevalence of any retinopathy was 28% vs 78% and the prevalence of any proliferative retinopathy was 2% vs 16%, respectively. The WESDR cohort is 99% white. Data indicate a higher prevalence of retinopathy in Mexican Americans and blacks with T2DM compared with whites (Table 1), although the data reflect prevalence estimates from different time periods.[192,193]

Figure 4.

Prevalence of any retinopathy and proliferative retinopathy in persons with diabetes by type/onset and duration in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. (A) T1DM diagnosed at age <30 years. (B) T2DM diagnosed at age ≥30 years, taking and not taking insulin.

Incidence. The duration of diabetes is associated with the incidence and progression of retinopathy in those with younger-onset T1DM. In the WESDR, half of the people with <5 years of diabetes at baseline and no retinopathy (n = 317) went on to develop retinopathy 4 years later.[191] For those with >5 but <15 of years of diabetes at baseline, there were too few persons with no retinopathy at baseline to reliably calculate incidence by duration of diabetes; however, the longer the duration of diabetes, the greater the incidence of progression over the following 4 years.[191] Within duration-specific groups, the incidence of retinopathy, proliferative retinopathy, and macular edema was higher in Mexican Americans with T2DM than in whites.[194]

Risk Factors

Glycemia. The WESDR (Figure 5), DCCT, and the Epidemiology of Diabetes Interventions and Complications (EDIC) studies confirmed the role of glycemic control as a critical risk factor preceding the development and progression of DR in persons with T1DM.

Figure 5.

Test of trend P < 0.001 for both groups.

The UKPDS[195] and the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Eye studies made the same conclusion regarding persons with T2DM.[1,196–198] One can see a decline in the levels of A1c when examining the trends over >30 years of follow-up of the group with T1DMin the WESDR (Table 2).[196]

ACCORD-Eye was a substudy of the ACCORD trial, a RCT comparing the effects of intensive glycemic control (A1c <6.0%) with standard glycemic control (A1c between 7.0% and 7.9%) that further randomized BP and lipid medication for high levels of each. The aim of this substudy was to examine the effects of the primary and secondary randomizations on the progression of DR in persons with T2DM. In a relatively short period (4 years), the study found a lower risk of DR progression (7.3%) in those in the intensive-glycemic-control group vs those in the standard-therapy group (10.4%) [adjusted OR 0.67; 95% confidence interval (CI): 0.51 to 0.87; P = 0.003].[190]

Researchers terminated the intensive glycemic-control phase of the ACCORD-Eye trial early because of a statistically significant 22% increase in overall mortality in the intensive glycemic-control group[196] of the larger study. This early closure of the intensive glycemic-control phase diminished the power to observe a protective effect for the severe microvascular endpoints, such as proliferative DR and clinically significant macular edema, which usually evolve over a longer period. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, intensive blood glucose control did not have any effect on any of the retinopathy and vascular outcomes in patients with T2DM.[196]

The results of the UKPDS, ACCORD, ADVANCE, and the Veterans Affairs Diabetes trial[199] (a RCT of intensive glycemic control in people with T2DM) have advanced the way we think about managing hyperglycemia in people with T2DM. For intensive therapy, the American Diabetes Association Guidelines suggest a target A1c level of 7.0% to reduce the risk of visual loss from DR in persons with diabetes. Clinicians most likely used this guideline to help people with T2DM manage glycemia, as the National Health and Nutrition Examination Survey reported that the number of people with T2DM taking three or more hypoglycemic drugs increased from 1999 to 2006.[200] This has been accompanied by a decrease in mean A1c from 7.8% to 7.2% from 1996 to 1997 and an increase in the percentage (from 40% in 1996 to 1997 to 54% in 2004 to 2006) of persons aged 40 years or older with T2DMthat had A1c levels <7%.[200] Data from the ACCORD and ADVANCE trials and Veterans Affairs Diabetes trial suggest the need to tailor intensive treatment to the individual, especially in patients with long-standing T2DM who have or who are at risk for developing cardiovascular disease (CVD). The findings from these studies may lead to a reduction in the number of persons with T2DM meeting the American Diabetes Association Guidelines of having an A1c of <7%.

Hypertension. Uncontrolled hypertension in persons with both T1DM and T2DM is associated with both DR[201] and DN.[202] Data suggest that its effect on blood flow damages the retinal capillary endothelial cells, resulting in the development and progression of DR.[203]

The UKPDS was designed to test whether lowering BP is beneficial in reducing macrovascular and microvascular complications associated with T2DM.[204] The study assigned hypertensive participants (defined at the time of the start of the trial in the 1980s as having a mean BP reading of 160/94 mm Hg) to tight BP control (aiming for <150/<85 mm Hg) and initial captopril or atenolol treatment (adding other agents as needed) or to less-tight BP control (aiming for <180/<105 mm Hg). Tight BP control resulted in a 35% reduction in retinal photocoagulation compared with the less-tight control group. After 7.5 years of follow-up, there was a 34% reduction in the rate of retinopathy progression and a 47% reduction in the deterioration of visual acuity. Atenolol and captopril were equally effective in reducing the risk of developing these microvascular complications, suggesting that BP reduction was more important than the type of medication used to reduce it. The effects of BP control were independent of the effects of glycemic control. These findings support the recommendations for BP control in patients with T2DM as a means of preventing visual loss from DR. Two years after completing the trial, follow-up of the UKPDS cohort showed that the reduction in BP was not sustained in the group that received tight BP control.[205] This was associated with loss of reductions in relative risk present during the trial for diabetes-related end points, such as death, microvascular disease, and stroke in the group receiving tight BP control, as compared with the group receiving less-tight BP control.

In the ACCORD study, hypertensive persons with T2DM were randomized to intensive BP treatment targeted to lowering the systolic BP to <120 mm Hg or to standard treatment targeted to maintaining systolic BP <140 mm Hg.[206] The average systolic BP was 119mm Hg in the intensive group and 133 mm Hg in the standard group. Despite this 14 mm Hg difference, intensive BP control was not associated with decreased progression of DR, nor was it associated with a reduction in the hazard of developing moderate loss of vision.[206] There were no statistically significant interactions with glycemic or lipid control.

Other RCTs have targeted specific types of antihypertensive agents, such as renin angiotensin system blockade. The EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes Mellitus reported a borderline beneficial effect of renin angiotensin system blockade on the progression of DR in patients with T1DM, independent of BP.[207] The Renin-Angiotensin System Study showed that the angiotensin-converting enzyme inhibitor enalapril and the Ang II receptor blocker (ARB) losartan were both associated with a reduced progression of retinopathy compared with those not randomized to BP medications, but these agents were not associated with the progression of nephropathy in subjects with T1DM.[100] However, the Diabetic Retinopathy Candesartan Prevent and Protect trials reported that candesartan cilexetil did not result in a statistically significant reduction in the progression of DR in persons with T2DM (P = 0.0508) or in the incidence or progression in those with T1DM.[208,209] Neither the ACCORD nor the ADVANCE studies found that lowering BP in those with mild hypertension or in those already normotensive was of benefit in preventing the incidence and progression of DR.

Together, these data suggest that lowering BP in those who have poorly controlled hypertension provides the greatest benefit in preventing the progression of retinopathy, as shown in the UKPDS. The type of antihypertensive medication used was less important; however, the renin angiotensin system blockade had the greatest efficacy in those with T1DM at moderate risk of DR progression. Aggressive BP control < 120 mm Hg was not indicated in persons with T2DM with mild or no hypertension. The American Diabetes Association recommends that people with hypertension should be treated to a systolic BP goal of <140 mm Hg and that patients with BP >120/80 mm Hg should be advised on lifestyle changes to reduce BP.[210]

Serum lipids. Epidemiological studies have associated serum total and low-density lipoprotein (LDL) cholesterol and triglycerides with the severity of DR and diabetic macular edema.[211–214] In the Early Treatment Diabetic Retinopathy Study, persons with higher levels of serum triglycerides, LDL cholesterol, and very LDL cholesterol at baseline had a 50% increased risk of developing hard exudates in the macula and decreased visual acuity and a 23% increased risk of developing proliferative DR.[206] In the DCCT/EDIC Study, those with higher serum total cholesterol, LDL cholesterol, and triglycerides (fourth vs first quartile range) had a two- to threefold increase in the odds of developing macular edema.[215]

Pilot studies to examine the efficacy of statin therapy in preventing or reducing the severity of macular edema have suggested a possible short-term benefit.[216–218] In the Fenofibrate Intervention and Event Lowering in Diabetes Study, fenofibrate was shown to reduce the need for laser treatment of DR in persons with T2DM(hazard ratio 0.69 95% CI: 0.56, 0.84, P = 0.0002), although the effect was not clearly due to lowering of plasma lipid concentrations.[219] Fenofibrate (in the context of simvastatin use in the ACCORD-Eye study) was associated with a significant decrease in the three-step or greater group [6.5% in the fenofibrate group vs 10.2% in the placebo group (hazard ratio 0.60 95% CI: 0.42 to 0.87, P<0.006)]. There was no effect on moderate vision loss. A recent study, which used the Health Core Integrated Research Database SM containing administrative claims data for >35 million Americans, examined microvascular complications of diabetes (e.g., DR and DN). The incidence of microvascular complications of diabetes was lower in patients who attained their goal of lower serum LDL cholesterol, higher serum high-density lipoprotein cholesterol, and lower serum triglycerides compared with those who did not.[220] In summary, accumulating evidence suggests that lipid lowering may have a role in limiting the development and progression of DR and macular edema, but the pathways leading to this protective effect are still unclear.

Other risk factors. There is evidence, mostly from clinical studies, that AGEs and oxidative stress are associated with complications of diabetes. AGEs result from the long-term exposure of proteins and lipids to hyperglycemia (via nonenzymatic glycation of these molecules). AGEs have been identified in renal lesions of persons with nephropathy as well as in atherosclerotic streaks in large blood vessels in persons with diabetes.[221–224] The accumulation of AGEs in people with diabetes is thought to lead to retinopathy, nephropathy, neuropathy, CVD, and cognitive dysfunction by directly damaging the tissue. AGEs may also lead to increased oxidative stress, endothelial dysfunction, inflammation, thrombosis, and fibrinolysis, and they adversely affect the RAS. All of these processes are hypothesized to be pathogenetic mechanisms for these complications.[93,222,225–228] Some, but not all, clinical studies have associated serum AGEs with diabetic complications, independent of A1c levels.

The body normally generates oxidizing compounds as an important component of the inflammation and tissue repair processes.[229,230] It represents part of the normal defense mechanism against invading microorganisms and malignant cells and occurs during tissue healing and remodeling. The retina exists in a highly oxidizing environment and is thought to be especially vulnerable to oxidative stress. Animal studies have shown a beneficial effect of antioxidants (e.g., nicanartine, vitamin E, and ALA) on retinopathy lesions in diabetic animals, suggesting that oxidative stress may be involved in the pathogenesis of DR.[231–233] Data from some studies have led researchers to hypothesize that oxidative stress in persons with diabetes is involved in the pathogenesis of not only DR but also DN, myocardial infarction, and cognitive dysfunction.[234–240] Oxidative stress in those with diabetes has been attributed to hyperglycemia with an increase in ROS through glucose auto-oxidation, nonenzymatic protein glycation, decreased antioxidant status, and reduced ROS removal.[241]

Genetic factors. Studies have reported familial clustering of DR, and this is compatible with the notion that genetic factors may contribute to developing DR.[242,243] It is possible that similarities in retinopathy severity within families are related to how genes affect glycemia and BP.[244,245] Control of these factors may influence the apparent effect of genes on retinopathy. Also, because retinal microaneurysms and blot hemorrhages are not specific to diabetes, their presence (in the absence of signs of more severe retinopathy) may lead to misclassification, resulting in inconsistent associations of candidate genes with early stages of DR compared with more severe stages of DR.[246]

DR has been associated with mitochondrial genes,[69,247] an AR gene,[69,248] endothelial NOS,[249] paraoxonase (an enzyme that prevents oxidation of LDL cholesterol),[250] tumor necrosis factor-βNcoI gene,[251]ε4 allele of the apolipoprotein E gene,[252] intercellular adhesion molecule-1,[253]α2β1 integrin gene (involved with platelet function),[254] and cytokine VEGF genes, but subsequent studies have not consistently replicated these associations.[255,256] Two recent studies, one a meta-analysis[257] and one from separate studies in France and Denmark,[258] failed to find definitive evidence of the effects of genes associated with serum levels of VEGF on DR.

Comorbidity and Mortality

In the WESDR, the risk of developing systemic complications (e.g., myocardial infarction, stroke, lower extremity amputation, DN) was higher in those with proliferative DR compared with those with no or minimal retinopathy at baseline (Table 3).[259]

In those with T1DM, while adjusting for age and sex, DR severity was associated with all-cause and ischemic heart disease mortality. In persons with T2DM, DR severity was associated with all-cause and ischemic heart disease mortality, as well as with stroke.[260] After adjusting for systemic factors, these associations remained only for allcause and stroke mortality in persons with T2DM. These findings suggest that severe DR is an indicator for increased risk of death, and may identify individuals who should be under care for CVD. Other studies have reported this finding.[261–263] The higher risk of CVD in persons with more severe DR may be partially due to the association of severe retinopathy with CVD risk factors, such as hyperglycemia, hypertension, platelet aggregation, and chronic renal disease.

Prevention of Incidence or Progression of DR

The primary method currently used to prevent or retard the progression of DR is the judicious use of hypoglycemic agents. However, there is evidence that other treatments may also be protective. As noted previously, studies have reported that angiotensin-converting enzyme inhibitors targeting the RAS,[100,204,207] as well as fenofibrate,[206,219] reduce the risk of progression of DR in those who are normotensive, independent of changes in BP and the lowering of uncontrolled BP (regardless of the antihypertensive medication used). However, RCTs of inhibitors of AR, PKC, and metalloproteinases have not shown efficacy in preventing the incidence and progression of DR in persons with diabetes.[264]

Current Treatment of Severe DR

Standard treatment of proliferative DR is still panretinal photocoagulation;[265] for diabetic macular edema it is focal laser treatment.[266] RCTs have shown the efficacy of intravitreally administered VEGF inhibitors[267] and steroids in treating proliferative DR and diabetic macular edema.[268] However, steroid injections are associated with increased risk of high intraocular pressure,[269] glaucoma,[270] and cataract surgery.[271] There are times when retinopathy is so severe that vitrectomy is needed to attempt to maintain or restore vision after the nonresolution of a vitreous hemorrhage and to decrease the risk of tractional retinal detachment.[272] Such treatment, although not without its own risks, has been found (on average) to be successful in maintaining visual function[273] and is still the best alternative for late-stage proliferative disease.

Summary

Although there is strong evidence of the efficacy of intensive glycemic and BP control in persons with diabetes, and therapeutic guidelines for these treatments exist, recent findings from clinical trials suggest the each person be treated individually, balancing microvascular andmacrovascular risk against the risk of hypoglycemia and CVD mortality. The ACCORD trial clearly taught us that there is no single recipe for the glycemic management of CVD risk in T2DM. The old principles still hold: treat each patient as an individual and first do no harm.[274]

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