In diabetic patients undergoing phacoemulsification cataract extraction with intraocular lens implantation, rapid improvement in glycemic control was associated with a higher rate of progression of diabetic macular edema, and probably should be avoided.47

4.2.2 Glycemic Variability

Besides the absolute level of glycemic control, there has been speculation that variability in glycemic control may be a factor in some retinopathy end points.48 In a study of 100 patients followed for 11 years, the incidence of PDR in type 1 diabetics was not related to glycemic variability as assessed by the standard deviation of the blood glucose concentration.48

4.2.3 Insulin Use in Type 2 Diabetes

Type 2 diabetics may be managed with diet alone, with diet plus oral agents, or in more difficult cases with both of these plus insulin. Use of insulin has

been associated with an increased prevalence of diabetic retinopathy and incidence of DR.11–13,36,49,50,18

4.2.4Pancreas and Pancreas–Renal Transplantation

Although normoglycemia can markedly improve ophthalmic outcomes when achieved earlier in the course of diabetic retinopathy, most patients who come to isolated pancreas transplantation or combined pancreas–renal transplantation have advanced retinopathy.51,52 Studies have not shown a difference in change in visual acuity, change in retinopathy severity, or need for laser treatment in patients receiving combined renal–pancreas transplants versus renal transplantation alone or in patients receiving isolated pancreatic transplants.51–53 Therefore, even if normoglycemia is achieved in such patients, the retinopathy may be too advanced to benefit. The number of patients with milder levels of retinopathy

undergoing transplantations is small, however, and it remains a possibility that they will show slower retinopathy progression.

4.2.5 Blood Pressure

Theoretically, blood pressure might be expected to be an important factor in diabetic retinopathy incidence and progression given the impaired autoregulatory capacity of the retinal vasculature in diabetic retinopathy.54 In such a state, higher blood pressure leads to higher pressure within the retinal capillaries and would be expected to promote macular edema.55 Indeed, in type 2 diabetic Pima Indians, a strong association of higher blood pressure with development of retinal exudates has been reported.56 In multivariate analyses in type 1 DM, higher systolic BP was associated with a higher 25-year incidence of DME.24 The hazard ratio per 10 mmHg increase in baseline systolic BP was 1.15 (95% CI 1.04–1.26, P ¼ 0.004).24 Higher diastolic BP was associated with an increased 10-year incidence of DME in a univariate analysis, but the relationship vanished in multivariate analysis after controlling for other baseline variables.23

Although the pathophysiologic pathway between elevated blood pressure and other aspects of DR is less clear, in the Wisconsin Epidemiologic Study of Diabetic Retinopathy, progression to PDR and baseline severity of retinopathy were associated with baseline diastolic blood pressure in type 1 diabetics.16 The risk of progression to PDR increased from 3 to 20% for those with diastolic blood pressure in the lowest versus highest quartiles at baseline.57 Epidemiologic evidence exists associating higher systolic blood pressure and prevalence and severity of diabetic retinopathy in both types 1 and 2 DM and seems to be a particular

important factor when the glycemic control is poorer (interaction).14–16,36 Incidence of DR over

9.4 years of follow-up increased in patients with concomitant hypertension.19 The adjusted odds ratio for the hypertensive group was 2.36 (95% CI 1.02–5.49) for the hypertensive group compared to the nonhypertensive group.19 In the Barbados Eye Study, the 4-year incidence of DR increased in patients with elevated systolic blood pressure.18 In

a cross-sectional study, severity of retinopathy was associated with higher systolic blood pressure.38 A

diagnosis of hypertension has been associated with an increased prevalence of DR.36,58 But not all stu-

dies have found an association between hypertension and prevalence of diabetic retinopathy, pro-

gression of retinopathy, or progression to

PDR.7,50,11,5,38,59,60

The importance of blood pressure for diabetic retinopathy outcomes has also been noted in randomized controlled trials in both types 1 and 2 diabetics. In the EDIC study involving patients with type 1 diabetes, the risk of further progression of retinopathy increased significantly with higher mean blood pressure at DCCT closeout (11% increase in risk per 5 mmHg increase in mean blood pressure; P < 0.001).32 The UKPDS contained a trial within a trial in which 758 patients with type 2 diabetes mellitus were randomized to tight blood pressure control and 390 patients to less tight blood pressure control.61 Over a median follow-up of 8.4 years the mean differences in systolic and diastolic blood pressure of the two groups were 10 and 5 mmHg, respectively.61 The mean HbA1c of the two groups was no different over this time. The group with tight blood pressure control had a 35% reduction in the risk of retinal photocoagulation (78% of which was for DME), a 34% reduction in risk of 2-step progression of retinopathy severity level on graded fundus photographs, a 47% reduction in the risk of losing three or more lines of best corrected visual acuity on the ETDRS chart, and

significant reductions in incidence of microaneurysms, hard exudates, and cotton wool spots.55,61,62

The visual acuity outcome has been attributed primarily to the beneficial effect of tighter blood pressure control on rates of development and progression of diabetic macular edema. No differences in rates of vitreous hemorrhage, blindness, and cataract extraction were detected between groups. Whether the blood pressure was lowered with a beta blocker

(atenolol) or an angiotensin-converting enzyme inhibitor (captopril) did not matter.62,63

Reduction in blood pressure also appears to be beneficial for type 2 diabetics who do not meet the conventional definition of hypertension – that is, systolic blood pressure >140 mmHg or diastolic blood pressure > 90 mmHg. In a randomized controlled trial comparing antihypertensive treatment with no treatment in normotensive type 2 diabetics,

lowering systolic blood pressure by a mean of 9 mmHg and diastolic blood pressure by a mean of 6 mmHg over 5 years led to a reduction in progression of retinopathy from 46 to 34% for the treated versus control groups, respectively (P ¼ 0.02).64 Changes not reaching statistical significance were also noted in number of patients developing retinopathy from no retinopathy and in percentage of patients developing proliferative retinopathy.64

Evidence exists for a similar beneficial effect of lower blood pressure and blood pressure reduction in type 1 diabetes, but is not as strong as for type 2 diabetes. In an observational study of younger type 1 diabetics, elevated diastolic blood pressure alone and in combination with elevated systolic blood pressure correlated significantly with more severe retinopathy and was associated with progression of retinopathy.65 Further relevant evidence on blood pressure reduction in type 1 diabetics is reviewed in the section on drugs affecting the rennin–angiotensin system (see below).

Although clinical blood pressure readings are taken during the day, the possible effects of nocturnal blood pressure are also important. Nocturnal blood pressure is generally lower than daytime blood pressure. A nondipper is defined as a person in whom the nocturnal blood pressure is >0.9 times the daytime blood pressure, whether referring to diastolic or systolic blood pressure. In both types 1 and 2 diabetics who are normotensive and without renal impairment, severity of diabetic retinopathy has been associated with a decreased fall in nocturnal systolic blood pressure and nocturnal mean blood pressure, whereas no associations have been found with daytime blood pressure measurements.66,67

Despite the data demonstrating the importance of treating hypertension in patients with diabetic retinopathy, many ophthalmologists do not include blood pressure measurement in their routine care of diabetic patients thereby missing an opportunity to help to preserve sight and prevent cardiovascular adverse outcomes.68 In one study, only 65% of type 2 diabetic patients requiring focal/grid photocoagulation for DME had blood pressure <140/80 with or without treatment, a level deemed by the British National Institute for Health and Clinical Excellence as suboptimal.69 As with intensive glycemic control, more intensive antihypertensive therapy

requires great effort by the patient. Almost onethird of patients in the UKPDS required three or more drugs to adequately control their blood pressure. Concerns about nocturnal hypotension and possibly related nonarteritic ischemic optic neuropathy have led to recommendations to avoid taking antihypertensive medications before bedtime.70

4.2.6 Serum Lipids

Elevated serum lipids have been speculated to cause or exacerbate diabetic retinopathy by several mechanisms. Oxidized low-density lipoprotein cholesterol may be toxic to capillary endothelium and pericytes by stimulating inflammation and release of cytokines.71 They may increase serum viscosity and affect the fibrinolytic system.72,73 Observational and epidemiologic studies inconsistently support an asso-

ciation of aspects of diabetic retinopathy with elevated serum lipids.60,73,74 In a population-based epi-

demiologic study, univariate analysis showed a significant trend associating an increased severity of diabetic retinopathy and retinal hard lipid exudates with increased cholesterol in persons using insulin regardless of age, but this effect vanished in multivariate analysis.75 Similarly, multiple logistic regression of NPDR, PDR, and DME against mean total cholesterol showed no association in a multi-ethnic California health maintenance organization.36 The Veterans Affairs Diabetes Trial found no association of total cholesterol, LDL cholesterol, or HDL cholesterol with baseline retinopathy severity.38 The Blue Mountains Eye Study found no association of baseline HDL cholesterol, total cholesterol, or triglycerides with progression of retinopathy.60 A case series found that patients with significant hard lipid exudates had higher levels of serum triglycerides but not cholesterol compared to patients without such exudates.74 In Korean type 2 diabetics, those with PDR had a higher lipoprotein (a) level than those without PDR after controlling for other factors associated with PDR.76

In the ETDRS, increased baseline cholesterol or low-density lipoproteins were associated with a higher frequency of hard exudates that were in turn associated with increased risk of visual loss.77 Thus, by a chain of reasoning, but not by a direct

study result, elevated serum lipid levels are indirectly associated with an increased risk of visual impairment from DME.71 Multiple reports suggest that lipid-lowering therapy can reduce retinal hard

exudates, but effects on visual acuity are inconsistent.78,79 A diet restricted in animal fat and supple-

mented with unsaturated fat (corn oil diet) has been shown to reduce the severity of retinal hard lipid exudates. No beneficial effect on visual acuity was noted, although possibly because of the small number of participants.80 Such diets are associated with reduced serum cholesterol and lipid levels. Oral clofibrate with or without androsterone is effective in reducing the severity of hard exudates in patients with diabetic retinopathy while simultaneously lowering serum cholesterol in patients with elevated baseline cholesterol.78,81 Treatment did not affect visual acuity nor did it slow progression to proliferative retinopathy.78,81

In persons with type 1 diabetes mellitus, severity of retinopathy is positively associated with triglycerides and negatively associated with HDL cholesterol. Using nuclear magnetic resonance analysis of whole serum to determine concentrations of 15 different lipoprotein subclasses by particle size, diabetic retinopathy is negatively associated with VLDL size.82 In a separate study of type 1 diabetes, high triglycerides and high LDL at baseline were also associated with subsequent progression of retinopathy at 2 years follow-up.83 In the DCCT, the total-to-HDL cholesterol ratio and the LDL predicted development of CSME and retinal hard exudates after controlling for known confounders.6 There were no associations of multiple lipid variables and other end points such as PDR and 3-step progression of retinopathy.6 In EDIC, the 3-step progression of retinopathy was significantly higher in patients with hyperlipidemia at DCCT closeout (70% increase in risk for those with hyperlipidemia versus those without; P ¼ 0.001).32 In WESDR among patients with younger onset diabetes, there was no association of baseline serum lipids and DME after controlling for HBA1c and other risk factors.84 An elevated serum triglyceride level was a predictor of progression to PDR in a study of type 1 DM.7

Response of DME to focal/grid laser photocoagulation may depend on levels of various serum lipid fractions. In a retrospective study of 65 eyes

Fig. 4.6 OCTs illustrating the potential exacerbation of DME by pregnancy and the potential spontaneous resolution once delivery occurs. This 37-year-old woman had previously been treated with focal/grid laser photocoagulation for DME of the left eye with resolution. She became pregnant in July of 2008 and over the course of pregnancy experienced recurrent

DME (left panel) that was observed rather than treated. The corrected visual acuity dropped from 20/25 to 20/32 during the pregnancy. She had an uneventful delivery in April of 2009, and at follow-up in May 2009, the pregnancy associated DME had spontaneously resolved with return of visual acuity to 20/25 (right panel)

DME that can resolve spontaneously after delivery (Fig. 4.6).101,102 Development and progression of

capillary nonperfusion is irreversible and can permanently impair visual acuity.101 The progression of retinopathy during pregnancy is related to baseline retinopathy at conception with faster progression seen in patients with more advanced retinopathy.103 Poorer glycemic control at conception and faster improvement early in pregnancy are additional risk factors associated with higher risk of progression of retinopathy.104 There can be spontaneous regression of changes in nonproliferative retinopathy and even proliferative retinopathy after delivery, but if highrisk proliferative retinopathy develops, panretinal laser photocoagulation is indicated rather than observation with anticipation of spontaneous post-

partum regression.105,106 Proliferative diabetic retinopathy can develop rapidly, and more frequent ophthalmoscopic monitoring is required during pregnancy, especially when simultaneous hypertension exacerbates the situation.101 Panretinal laser photocoagulation should be applied for high-risk PDR and appears as effective as in patients with similar degrees of retinopathy who are not pregnant.101 Fetal morbidity and loss is higher in patients with proliferative diabetic retinopathy, but an earlier general recommendation that proliferative retinopathy is an indication for therapeutic abortion is now considered unsupported by the improved prognosis for fetal survival and maternal eyesight associated with advances in medical care.107 The use of intraocular anti-VEGF drugs in the setting of pregnancy