Massimo Porta

Global prevalence and major risk factors of diabetic retinopathy

OBJECTIVE To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years. RESULTS A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A1c, and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials

BACKGROUND Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess whether candesartan could reduce the incidence and progression of retinopathy in type 1 diabetes. METHODS Two randomised, double-blind, parallel-design, placebo-controlled trials were done in 309 centres worldwide. Participants with normotensive, normoalbuminuric type 1 diabetes without retinopathy were recruited to the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned to candesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators and participants were unaware of the treatment allocation status. The primary endpoints were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbers NCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1. FINDINGS 1421 participants (aged 18-50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) in DIRECT-Prevent 1, and 1905 (aged 18-55 years) to candesartan (n=951) or to placebo (n=954) in DIRECT-Protect 1. Incidence of retinopathy was seen in 178 (25%) participants in the candesartan group versus 217 (31%) in the placebo group. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in the placebo group. Hazard ratio (HR for candesartan vs placebo) was 0.82 (95% CI 0.67-1.00, p=0.0508) for incidence of retinopathy and 1.02 (0.80-1.31, p=0.85) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0.65 (0.48-0.87, p=0.0034), which was attenuated but still significant after adjustment for baseline characteristics (0.71, 0.53-0.95, p=0.046). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1.16, 95% CI 1.05-1.30, p=0.0048) and DIRECT-Protect 1 (1.12, 95% CI 1.01-1.25, p=0.0264). Adverse events did not differ between the treatment groups. INTERPRETATION Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression.

Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial

BACKGROUND Diabetic retinopathy remains a leading cause of visual loss in people of working age. We examined whether candesartan treatment could slow the progression and, secondly, induce regression of retinopathy in people with type 2 diabetes. METHODS We did a randomised, double-blind, parallel-group, placebo-controlled trial in 309 centres worldwide. We recruited normoalbuminuric, normotensive, or treated hypertensive people with type 2 diabetes with mild to moderately severe retinopathy and assigned them to candesartan 16 mg once a day or placebo. After a month, the dose was doubled to 32 mg once per day. Investigators and patients were unaware of the treatment allocation status. Progression of retinopathy was the primary endpoint, and regression was a secondary endpoint. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00252694. FINDINGS 1905 participants (aged 37-75 years) were randomised to candesartan (n=951) or placebo (n=954). 161 (17%) patients in the candesartan group and 182 (19%) in the placebo group had progression of retinopathy by three steps or more on the Early Treatment Diabetic Retinopathy Study scale. The risk of progression of retinopathy was non-significantly reduced by 13% in patients on candesartan compared with those on placebo (hazard ratio [HR] 0.87, 95% CI 0.70-1.08, p=0.20). Regression on active treatment was increased by 34% (1.34, 1.08-1.68, p=0.009). HRs were not attenuated by adjustment for baseline risk factors or changes in blood pressure during the trial. An overall change towards less severe retinopathy by the end of the trial was observed in the candesartan group (odds 1.17, 95% CI 1.05-1.30, p=0.003). Adverse events did not differ between the treatment groups. INTERPRETATION Treatment with candesartan in type 2 diabetic patients with mild to moderate retinopathy might induce improvement of retinopathy.

Effect of Candesartan on Microalbuminuria and Albumin Excretion Rate in Diabetes: Three Randomized Trials

BACKGROUND Microalbuminuria in diabetes is strongly predictive of nephropathy, end-stage renal disease, and premature cardiovascular morbidity and mortality. Effective preventive therapies are therefore a clinical priority. OBJECTIVE To determine whether the angiotensin-receptor blocker candesartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes. DESIGN 3 randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program. SETTING 309 secondary care centers. PATIENTS 3326 and 1905 patients with type 1 and type 2 diabetes, respectively. Most were normotensive, and all had normoalbuminuria (median urinary albumin excretion rate, 5.0 microg/min). INTERVENTION Candesartan, 16 mg/d increasing to 32 mg/d, versus placebo. Assignment was done centrally using an interactive voice-response system. Patients, caregivers, and researchers were blinded to treatment assignment. During a median follow-up of 4.7 years, 793 patients discontinued therapy and 63 were lost to follow-up. MEASUREMENTS Urinary albumin excretion rate, assessed annually by 2 overnight collections; if it was 20 microg/min or greater, then 2 further collections were done. The primary end point was new microalbuminuria (3 or 4 collections of urinary albumin excretion rate >or=20 microg/min). The secondary end point was rate of change in albuminuria. RESULTS Individual and pooled results of the 3 trials showed that candesartan had little effect on risk for microalbuminuria (pooled hazard ratio, 0.95 [95% CI, 0.78 to 1.16]; P = 0.60). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73% to 10.14%; P = 0.024) with candesartan than with placebo. LIMITATIONS Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk, which resulted in a low rate of microalbuminuria. Studies were powered for retinal and not renal end points. CONCLUSION Candesartan, 32 mg/d, for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes.

Diabetic retinopathy: A clinical update

Abstract. Easy observation of the fundus oculi makes retinopathy the most frequently reported chronic complication of diabetes and, consequently, the one we know best in terms of epidemiology and natural history. Achieving near-normal levels of blood glucose and blood pressure provides empirical though powerful tools for clinicians to delay the onset and progression of diabetic retinopathy. Even when these measures have failed and retinopathy becomes sight-threatening, laser photocoagulation has proven remarkably effective. Nonetheless, retinopathy remains a leading cause of blindness and there is little evidence that diabetes-related visual loss is decreasing in industrialized countries. This may result from the mixed blessing of prolonged survival of patients who had become diabetic when metabolic control was pursued less fastidiously than today. Screening for sight-threatening retinopathy is the most cost-effective medical procedure known and should help optimise the use of diagnostic and therapeutic resources, but its widest deployment still meets with inertia and lack of interest within most health care systems. Improving clinical skills and technology, however, allow us to take a more optimistic look at the future, as pathogenesis-targeted forms of treatment are being developed and tested through appropriately powered clinical trials.

Relationship between risk factors and mortality in type 1 diabetic patients in Europe : the EURODIAB Prospective Complications Study (PCS)

OBJECTIVE—The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—Baseline risk factors were measured in the EURODIAB Prospective Cohort Study with 2,787 type 1 diabetic patients (51% men and 49% women) recruited from 16 European countries. Mortality data were collected during a 7-year follow-up. RESULTS—There was an annual mortality rate of 5 per 1,000 person-years in patients with type 1 diabetes (mean age at baseline 33 years, range 15–61 years); of the total 2,787 subjects, 102 died. The final multivariable model contained age at baseline (standardized hazard ratio 1.78 [95% CI 1.44–2.20]), A1C (1.18 [0.95–1.46]), waist-to-hip ratio (WHR) (1.32 [1.14–1.52]), pulse pressure (1.33 [1.13–1.58]), and non-HDL cholesterol (1.33 [1.12–1.60]) as risk factors for all-cause mortality. Macroalbuminuria (2.39 [1.19–4.78]) and peripheral (1.88 [1.06–3.35]) and autonomic neuropathy (2.40 [1.32–4.36]) were the most important risk markers for mortality. Similar risk factors were found for all-cause, non-cardiovascular disease (CVD), unknown-cause, and CVD mortality. CONCLUSIONS—Important risk factors for the increased total and non-CVD mortality in type 1 diabetic patients are age, WHR, pulse pressure, and non-HDL cholesterol. Microvascular complications from macroalbuminuria and peripheral and autonomic neuropathy are strong risk markers for future mortality exceeding the effect of the traditional risk factors.

Risk factors for progression to proliferative diabetic retinopathy in the EURODIAB Prospective Complications Study

Aims/hypothesis: Proliferative diabetic retinopathy (PDR), a leading cause of blindness, cannot be totally prevented by optimizing metabolic and blood pressure control and responds to no specific treatment other than partially destructive retinal photocoagulation. Recognizing risk factors using large-scale epidemiological studies could help identify targets for treatment. The EURODIAB Prospective Complications Study (PCS) includes the largest cohort so far of patients with Type I (insulin-dependent) diabetes mellitus. Methods: Baseline data were collected between 1989 and 1991 on 3250 patients who were recalled for follow-up. Physical examination, biochemical tests and assessment of complications were done on both occasions. In particular, 1249 patients had retinal photographs taken both basally and after an average of 7.3 years. Results: Proliferative retinopathy had developed in 157 patients (cumulative incidence 17.3/1000 patient-years; 95 %-CI: 13.6–21.1). HbA1 c (standardized regression estimate – SRE = 3.03, CI 2.49–3.69), diabetes duration (1.71, 1.42–2.06), age at diagnosis < 12 (1.66, 1.11–2.50), diastolic blood pressure less than or equal to 83 (1.50, 1.03–2.20) and waist-to-hip ratio (1.50, 1.03–2.20) were all independent predictors for progression to PDR when entered simultaneously into a logistic regression model. Including retinopathy at baseline maintained the effects of metabolic control and pre-pubertal onset only. Including the albumin excretion rate maintained the effect of control but reduced SRE for pre-pubertal onset to 1.49 (0.94–2.33). There was no evidence for a threshold effect for HbA1 c concentrations at baseline and progression to proliferative retinopathy. Conclusion/hypothesis: Metabolic control and duration of diabetes are strong indicators of progression to proliferative retinopathy. Onset of diabetes before puberty could be an additional independent risk factor. [Diabetologia (2001) 44: 2203–2209]

Diabetic microvascular complications: can patients at risk be identified? A review

People with diabetes have an increased risk of developing microvascular complications, diabetic retinopathy, diabetic nephropathy and diabetic neuropathy, which, if undetected or left untreated, can have a devastating impact on quality of life and place a significant burden on health care costs. In addition, diabetic microvascular complications can reduce life expectancy. The strongest risk factors are glycaemic control and diabetes duration; however, other modifiable risk factors such as hypertension, hyperlipidaemia and smoking, and unmodifiable risk factors including age at onset of diabetes and genetic factors may all play a part. Along with the presence of external risk factors, some associations have also been noted between diabetic microvascular complications themselves. There is evidence that diabetic retinopathy in association with increased blood pressure is an important risk factor for diabetic nephropathy progression. Significant correlations have also been shown between the presence of diabetic peripheral neuropathy and the presence of background or proliferative diabetic retinopathy. Clinical trials are currently in progress looking at a number of approaches to designing treatments to prevent the adverse effects of hyperglycaemia. It is essential however, that risk factors associated with the progression and development of diabetic microvascular complications are detected and treated at an early stage in order to further reduce morbidity and mortality. Considering all three complications as interrelated may well facilitate early detection of microvascular disease.

CIRCULATING PROSTACYCLIN MAY BE REDUCED IN DIABETES

remained high, iron-binding proteins were fully saturated, and his cardiomyopathy was worsening; continuous subcutaneous infusion of desferrioxamine was felt to be an appropriate treatment. With a portable syringe-pump (Mill Hill infuser, Muirhead Ltd, Beckenham, Kent) 900 mg desferrioxamine dissolved in sterile 0-154 mol/1 saline, was infused daily through a cannula (21 gauge butterfly) implanted in the s.c. tissue of the anterior abdominal wall. Over 10 days 6-61 mmol (370 mg) of iron were excreted in the urine. This is equivalent to venesecting 700-800 ml of blood. It is possible that iron removal could be increased further by using a higher dose of desferrioxamine (up to 4 g/24 h) and/or the addition of ascorbic acid.4

Rethink Organization to iMprove Education and Outcomes (ROMEO): A multicenter randomized trial of lifestyle intervention by group care to manage type 2 diabetes

OBJECTIVE A trial was performed to establish whether our group care model for lifestyle intervention in type 2 diabetes can be exported to other clinics. RESEARCH DESIGN AND METHODS This study was a 4-year, two-armed, multicenter controlled trial in 13 hospital-based diabetes clinics in Italy (current controlled trials no. ISRCTN19509463). A total of 815 non–insulin-treated patients aged <80 years with ≥1 year known diabetes duration were randomized to either group or individual care. RESULTS After 4 years, patients in group care had lower A1C, total cholesterol, LDL cholesterol, triglycerides, systolic and diastolic blood pressure, BMI, and serum creatinine and higher HDL cholesterol (P < 0.001, for all) than control subjects receiving individual care, despite similar pharmacological prescriptions. Health behaviors, quality of life, and knowledge of diabetes had become better in group care patients than in control subjects (P < 0.001, for all). CONCLUSIONS The favorable clinical, cognitive, and psychological outcomes of group care can be reproduced in different clinical settings.