Diabetic retinopathy predicts all-cause mortality and cardiovascular events in both type 1 and 2 diabetes: meta-analysis of observational studies

OBJECTIVE

The prognostic significance of diabetic retinopathy (DR) for death and cardiovascular (CV) outcomes is debated. We investigated the association of DR with all-cause mortality and CV events in patients with diabetes by a systematic review and meta-analysis.

RESEARCH DESIGN AND METHODS

The electronic databases Medline and Embase were searched for cohort studies that evaluated DR in type 2 or type 1 diabetic patients and reported total mortality and/or fatal and nonfatal CV events, including myocardial infarction, angina pectoris, coronary artery bypass graft, ischemic changes on a conventional 12-lead electrocardiogram, transient ischemic attack, nonfatal stroke, or lower leg amputation. Data extraction was performed by two reviewers independently. Pooled effect estimates were obtained by using random-effects meta-analysis.

RESULTS

The analysis included 20 studies that fulfilled the inclusion criteria, providing data from 19,234 patients. In patients with type 2 diabetes (n = 14,896), the presence of any degree of DR increased the chance for all-cause mortality and/or CV events by 2.34 (95% CI 1.96–2.80) compared with patients without DR. In patients with type 1 diabetes (n = 4,438), the corresponding odds ratio was 4.10 (1.50–11.18). These associations remained after adjusting for traditional CV risk factors. DR was also predictive of all-cause mortality in type 2 diabetes (odds ratio 2.41 [1.87–3.10]) and type 1 diabetes (3.65 [1.05–12.66]).

CONCLUSIONS

The presence of DR was associated with an increased risk of all-cause mortality and CV events in both type 2 and type 1 diabetic patients.Diabetic retinopathy (DR) is a common chronic microvascular diabetes complication. Approximately 29% of U.S. adults with type 2 diabetes have DR (1), whereas DR will develop in 95% of type 1 diabetic individuals during their lifetime (2). DR has been associated with increased all-cause and cardiovascular (CV) mortality risk in both type 2 and type 1 diabetes (3–7). Associations with DR have been more extensively evaluated in type 2 diabetes, whereas studies in type 1 diabetes are scarce.Considering these data, identification of DR could possibly add to the diabetic patient’s CV risk stratification. Furthermore, the fundus examination is inexpensive and is routinely performed for the screening of chronic diabetes complications. Therefore, it is worthwhile to comprehensively review data on the predictive role of DR. The aim of the current study was to investigate the association of DR with all-cause mortality and CV events (fatal and nonfatal) in type 2 and type 1 diabetic patients by a systematic review and meta-analysis of cohort studies.     

The effectiveness of beta-blockers after myocardial infarction in patients with type 2 diabetes

OBJECTIVE: Beta-blocker therapy has been proven to reduce mortality and reinfarction after myocardial infarction (MI), but the impact of beta-blockers on cardiac outcomes in patients with type 2 diabetes in routine practice is not clear. The purpose of this study was to determine the effectiveness of beta-blockers after MI in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using the Saskatchewan Health Databases, 12,272 patients with newly treated diabetes were identified between 1991 and 1996; 625 patients were subsequently admitted for MI. Beta-blocker exposure within 30 days of discharge was identified in 298 patients, and all were followed until death, coverage termination, or 31 December 1999. Multivariate proportional hazards models were used to assess differences in all-cause mortality, recurrent MI, and 30-day all-cause rehospitalization (the latter a proxy measure for drug safety). RESULTS: Patients were aged 69 +/- 11 years old, 66% were male, and mean follow-up was 2.7 +/- 2.1 years. Overall, beta-blockers were prescribed for 48% of patients. There were fewer deaths in the beta-blocker group versus control subjects (55 of 298 [18.5%] vs. 126 of 327 [38.5%], respectively, P < 0.001). However, beta-blockers were not associated with improved survival in multivariate analyses (hazard ratio [HR] 0.89 [95% CI 0.63-1.25]). There were no differences in rates of recurrent MI (adjusted HR 1.35 [0.93-1.95]) or rehospitalizations (adjusted odds ratio 1.40 [0.83-2.37]) between the groups. CONCLUSIONS: Beta-blocker therapy post-MI was not associated with reduced mortality or fewer recurrent events in people with type 2 diabetes in routine practice, although these medications were safe in this population.     

Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women

OBJECTIVE: To investigate the association of retinopathy with the risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in type 2 diabetic subjects in a population-based 18-year follow-up study with particular emphasis on sex differences. RESEARCH DESIGN AND METHODS: Our study cohort comprised 425 Finnish type 2 diabetic men and 399 type 2 diabetic women who were free of CVD at baseline. The findings were classified based on standardized clinical ophthalmoscopy to categories of no retinopathy, background retinopathy, and proliferative retinopathy. The study end points were all-cause, CVD, and CHD mortality. RESULTS: Adjusted Cox model hazard ratios (95% CIs) of all-cause, CVD, and CHD mortality in men were 1.34 (0.98-1.83), 1.30 (0.86-1.96), and 1.18 (0.74-1.89), respectively, for background retinopathy and 3.05 (1.70-5.45), 3.32 (1.61-6.78), and 2.54 (1.07-6.04), respectively, for proliferative retinopathy and in women 1.61 (1.17-2.22), 1.71 (1.17-2.51), and 1.79 (1.13-2.85), respectively, for background retinopathy and 2.92 (1.41-6.06), 3.17 (1.38-7.30), and 4.98 (2.06-12.06), respectively, for proliferative retinopathy. CONCLUSIONS: Proliferative retinopathy in both sexes and background retinopathy in women predicted all-cause, CVD, and CHD death. These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria. This suggests the presence of common background pathways for diabetic microvascular and macrovascular disease other than those included in the conventional risk assessment of CVD. The sex difference observed in the association of background retinopathy with macrovascular disease warrants closer examination.     

Adiponectin and all-cause mortality in elderly people with type 2 diabetes

OBJECTIVE To assess the association between serum adiponectin level and all-cause mortality in people with type 2 diabetes. Because of the insulin-sensitizing, anti-inflammatory, and antiatherogenic effects of adiponectin, we hypothesized that higher adiponectin level would be associated with lower all-cause mortality. RESEARCH DESIGN AND METHODS A total of 609 men and women aged 72 ± 6.3 years with type 2 diabetes and information on total and high molecular weight adiponectin were followed for a median of 5 years. The longitudinal association between adiponectin and all-cause mortality was analyzed with Cox proportional hazards models with time from adiponectin measurement to death as the time-to-event variable. Analyses were adjusted for demographic variables and significant diabetes parameters, significant cardiovascular parameters, and significant diabetes medications. RESULTS Total and high molecular weight adiponectin were highly correlated. The highest adiponectin quartile was strongly associated with higher all-cause mortality compared with the lowest quartile (hazard ratio = 4.0 [95% CI: 1.7-9.2]) in the fully adjusted model. These results did not change in analyses stratified by sex and thiazolidinedione use, after exclusion of people who died within one year of adiponectin measurement, or when change in weight before adiponectin measurement was considered. CONCLUSIONS Contrary to our hypothesis, higher adiponectin level was related to higher all-cause mortality. This association was not explained by confounding by other characteristics, including medications or preceding weight loss.     

Vitamin D levels, microvascular complications, and mortality in type 1 diabetes

OBJECTIVE

To evaluate vitamin D as a predictor of all-cause mortality, progression from normoalbuminuria to micro- or macroalbuminuria, and the development of background or proliferative retinopathy in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

A prospective observational follow-up study in which an inception cohort of type 1 diabetic patients was followed from onset of diabetes diagnosed between 1979 and 1984. Plasma vitamin D [25(OH)D3] levels were determined by high performance liquid chromatography/tandem mass spectrometry in 227 patients before the patients developed microalbuminuria. Values equal to or below the 10% percentile (15.5 nmol/L) were considered severe vitamin D deficiency.

RESULTS

Median (range) vitamin D was 44.6 (1.7–161.7) nmol/L. Vitamin D level was not associated with age, sex, urinary albumin excretion rate (UAER), or blood pressure. During follow-up, 44 (18%) patients died. In a Cox proportional hazards model, the hazard ratio for mortality in subjects with severe vitamin D deficiency was 2.7 (1.1–6.7), P = 0.03, after adjustment for UAER, HbA_1c, and conventional cardiovascular risk factors (age, sex, blood pressure, cholesterol, smoking). Of the 220 patients, 81 (37%) developed microalbuminuria and 27 (12%) of these progressed to macroalbuminuria. Furthermore, 192 (87%) patients developed background retinopathy, whereas 34 (15%) progressed to proliferative retinopathy. Severe vitamin D deficiency at baseline did not predict the development of these microvascular complications.

CONCLUSIONS

In patients with type 1 diabetes, severe vitamin D deficiency independently predicts all-cause mortality but not development of microvascular complications in the eye and kidney. Whether vitamin D substitution in type 1 diabetic patients can improve the prognosis remains to be investigated.Hypovitaminosis D is found to be highly prevalent worldwide (1). Recently, low levels of vitamin D have been associated with an increased risk of excess all-cause and cardiovascular mortality in the general population (2) as well as in type 2 diabetic patients (3). However, to our knowledge the association has never been investigated in type 1 diabetic subjects. The levels of plasma vitamin D (25-hydroxyvitamin D3 [25(OH)D3]) varies considerably among individuals mainly because of differences in sun exposure, skin color, and the presence of risk factors such as diabetes or other comorbidities.In patients with diabetes, an excess mortality in patients with diabetes complications has been established (4). Development and progression of diabetic microangiopathy in terms of retinopathy and nephropathy is known to be closely related to poor metabolic control, elevated arterial blood pressure, and other risk factors (5,6). Data from studies in experimental diabetic nephropathy indicate that vitamin D insufficiency may also be involved in the pathogenesis of albuminuria. In the general population, an inverse association is found between the level of vitamin D and the prevalence of albuminuria (7), and limited data from clinical trials in nondiabetic chronic kidney disease (CKD) patients suggest that treatment with paricalcitol (vitamin D receptor analog [VDRA]) may reduce proteinuria (8–10). Furthermore, recently published data suggest that administration of a VDRA on top of blockade of the rennin angiotensin aldosterone system (RAAS) in patients with type 2 diabetes and diabetic nephropathy lowers albuminuria (11). Diabetes is the leading cause of CKD and kidney failure in the Western world, but it is unclear if vitamin D insufficiency contributes to the risk of developing diabetic nephropathy or other microvascular complications. With this study we aimed to investigate whether very low levels of plasma 25(OH)D3 could predict increased risk of excess mortality as well as development of microvascular complications in type 1 diabetic patients.     

Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: the EURODIAB prospective complications study

OBJECTIVE: To study the relationship of nonproliferative and proliferative retinopathy with all-cause mortality and cardiovascular disease (CVD) incidence in type 1 diabetic patients and, additionally, the role of cardiovascular risk factors in these associations. RESEARCH DESIGN AND METHODS: This prospective study included 2,237 type 1 diabetic patients from 31 centers in 16 European countries at baseline, aged 15-60 years, who were examined for retinopathy by taking two-field 45 degrees fundus photographs, which were centrally graded. Mortality and cardiovascular morbidity follow-up was assessed 6-8 years after baseline examination according to a standardized protocol. RESULTS: After 7.9 years of follow-up, 64 patients had died and 128 patients had incident CVD. The age- and sex-adjusted hazard ratios (HRs) of all-cause mortality were 1.45 (95% CI 0.71-2.96) and 4.16 (1.96-8.84) in patients with nonproliferative and proliferative retinopathy at baseline, respectively. Adjustments for cardiovascular risk factors completely obliterated the association with nonproliferative retinopathy, whereas the association with proliferative retinopathy remained twofold increased, although nonsignificant. The age- and sex-adjusted HRs of incident CVD were 1.73 (1.15-2.60) and 2.05 (1.22-3.45) in patients with nonproliferative and proliferative retinopathy, respectively. After adjustments for cardiovascular risk factors, both associations were attenuated and lost statistical significance. CONCLUSIONS: This study shows that type 1 diabetic patients with nonproliferative or proliferative retinopathy have an increased risk for all-cause mortality and incident CVD. The presence of cardiovascular risk factors explained the associations to a large extent, except for the associations with proliferative retinopathy, which suggests that other shared mechanisms may be involved.     

Reduced mortality associated with the use of ACE inhibitors in patients with type 2 diabetes

OBJECTIVE: ACE inhibitor therapy is widely used in lower-risk patients with type 2 diabetes to reduce mortality, despite limited evidence to support this clinical strategy. The aim of this study was to evaluate the association between ACE inhibitor use and mortality in patients with diabetes and no cardiovascular disease. RESEARCH DESIGN AND SETTINGS: Using the Saskatchewan health databases, 12,272 new users of oral hypoglycemic agents were identified between the years of 1991 and 1996. We excluded 3,202 subjects with previous cardiovascular disease. Of the remaining subjects, 1,187 "new users" of ACE inhibitors were identified (ACE inhibitor cohort). Subjects not receiving ACE inhibitor therapy throughout the follow-up period served as the control cohort (n = 4,989). Subjects were prospectively followed until death or the end of 1999. Multivariate Cox proportional hazards models were used to assess differences in all-cause and cardiovascular-related mortality between cohort groups. RESULTS: Subjects were 60.7 +/- 13.7 years old, 43.6% female, and were followed for an average of 5.3 +/- 2.1 years. Mean duration of ACE inhibitor therapy was 3.6 +/- 1.8 years. We observed significantly fewer deaths in the ACE inhibitor group (102 [8.6%]) compared with the control cohort (853 [17.1%]), with an adjusted hazard ratio (HR) and 95% CI of 0.49 (0.40-0.61) (P < 0.001). Cardiovascular-related mortality was also reduced (40 [3.4%] vs. 261 [5.2%], adjusted HR, 0.63 [0.44-0.90]; P = 0.012). CONCLUSIONS: The use of ACE inhibitors was associated with a significant reduction in all-cause and cardiovascular-related mortality in a broad spectrum of patients with type 2 diabetes and no cardiovascular disease.     

Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes

BACKGROUND: The causes and mechanisms of increased mortality of patients with diabetic nephropathy are unclear, and its natural history is poorly understood. Aim: To evaluate risk factors for mortality in type 2 diabetic patients with nephropathy. DESIGN: Retrospective study of clinical and biochemical parameters in diabetic nephropathic patients and controls sampled from a secondary care register. METHODS: We studied 170 type 2 diabetic patients (from 1987 to 1995) with nephropathy (proteinuria >0.5 g/24 h) and 170 non-nephropathic patients. Follow-up was until death or December 1997. Details of demographics, clinical and treatment history were obtained from medical records. RESULTS: Mean follow-up was 5.3 years. Of the patients with nephropathy at baseline, 63 (37%) died compared with 14 (8%) non-nephropathic patients (chi(2)=53.8, p<0.0001). Age- and sex-adjusted all-cause mortality rates were 8.1 (6.4, 9.8) and 1.4 (0.5, 2.2) deaths per 100 person-years, respectively (rate ratio 5.8). Forty-four patients (57%) died from cardiovascular causes (rate ratio 5.4). Mortality was directly proportional to degree of proteinuria: 0.5-2 g/24 h, 4.6 (2.9-7.1); >2 g/24 h, 9.9 (7.3-13.5) per 100 patient-years. A 36% (5-78%) excess risk of mortality was observed for each log unit increase in proteinuria. Multivariate Cox regression analyses confirmed a five-fold excess risk for all-cause and cardiovascular mortality in patients with nephropathy compared with those without. This was independent of other risk factors including baseline age [5% (1-8%)/year], creatinine [2.5 (1.12-5.6)/10 micromol/l] and glycaemic control (HbA(1c)) [15% (1-31%) per 1% rise]. CONCLUSIONS: Proteinuria is a potentially preventable and reversible risk factor associated with high mortality in type 2 diabetic patients. Prevention of the development of overt nephropathy and improvement in diabetes control may reduce mortality in these patients.     

Improved clinical outcomes associated with metformin in patients with diabetes and heart failure

OBJECTIVE: Metformin is considered contraindicated in patients with heart failure because of concerns over lactic acidosis, despite increasing evidence of potential benefit. The aim of this study was to evaluate the association between metformin and clinical outcomes in patients with heart failure and type 2 diabetes. RESEARCH DESIGN AND METHODS: Using the Saskatchewan Health databases, 12,272 new users of oral antidiabetic agents were identified between the years 1991 and 1996. Subjects with incident heart failure (n = 1,833) were identified through administrative records based on ICD-9 code 428 and grouped according to antidiabetic therapy: metformin monotherapy (n = 208), sulfonylurea monotherapy (n = 773), or combination therapy (n = 852). Multivariate Cox proportional hazards models were used to assess differences in all-cause mortality, all-cause hospitalization, and the combination (i.e., all-cause hospitalization or mortality). RESULTS: Average age of subjects was 72 years, 57% were male, and average follow-up was 2.5 +/- 2.0 (SD) years. Compared with sulfonylurea therapy, fewer deaths occurred in subjects receiving metformin: 404 (52%) for sulfonylurea monotherapy versus 69 (33%) for metformin monotherapy (hazard ratio [HR] 0.70 [95% CI 0.54-0.91]) and 263 (31%) for combination therapy (0.61 [0.52-0.72]). A reduction in deaths or hospitalizations was also observed: 658 (85%) for sulfonylurea monotherapy versus 160 (77%) for metformin monotherapy (0.83 [0.70-0.99]) and 681 (80%) for combination therapy (0.86 [0.77-0.96]). There was no difference in time to first hospitalization between study groups. CONCLUSIONS: Metformin, alone or in combination, in subjects with heart failure and type 2 diabetes was associated with lower morbidity and mortality compared with sulfonylurea monotherapy.     

Assessing the impact of visual acuity on quality of life in individuals with type 2 diabetes using the short form-36

OBJECTIVE: We sought to ascertain quality-of-life measures and utility values associated with visual acuity in type 2 diabetes. RESEARCH DESIGN AND METHODS: The Medical Outcome Study Short Form with 36 items (SF-36) was administered to 4,051 individuals with type 2 diabetes who were enrolled in the Lipids in Diabetes Study, and their best attainable vision was determined using an Early Treatment of Diabetic Retinopathy Study chart, expressed as a LogMAR score. Eight domain scores and a utility value representing an overall quality-of-life score were calculated using predefined algorithms. The associations between quality of life measured and best-eye visual acuity were assessed graphically and by regression analysis. RESULTS: All eight SF-36 domain scores were negatively associated with reduced visual acuity. The impact of lower levels of visual acuity ranged from a decline of 1.3 units for a 0.1-LogMAR increase for physical functioning and 0.6 units in mental health. Regression analysis indicated a negative association (P < 0.001) between utility and reduced visual acuity after controlling for sex, BMI, smoking status, and history of diabetes complications. Patients whose LogMAR scores equated to legally blind had, on average, 0.054 (95% CI 0.034-0.074) lower utility compared with patients with normal visual acuity. CONCLUSIONS: Reduced visual acuity is negatively associated with quality of life. The utility scores estimated here should inform studies quantifying the burden of diabetes and those evaluating potential therapies for treating or preventing diabetic eye diseases.     

Survival in patients with type 2 diabetes in a Swedish community: skaraborg hypertension and diabetes project

OBJECTIVE: To explore risk factors for all-cause mortality in patients with type 2 diabetes treated in primary care. RESEARCH DESIGN AND METHODS:A prospective population-based study of 400 patients with type 2 diabetes who consecutively completed an annual checkup in primary care in Skara, Sweden, during 1992-1993. Vital status was ascertained to year 2000. Baseline characteristics as predictors for mortality were analyzed by Cox regression and expressed as relative risks (RRs), with 95% CIs. RESULTS: During a mean follow-up time of 5.9 years, 131 patients died (56 deaths per 1,000 patients per year). In both sexes, all-cause mortality was predicted by HbA(1c) (by 1%; RR 1.14, 95% CI 1.01-1.27), and by LDL-to-HDL cholesterol ratios (1.15, 1.00-1.32). Increased mortality was also seen with prevalent hypertension (1.72, 1.21-2.44), microalbuminuria (1.87, 1.27-2.76), and previous cardiovascular disease (1.70, 1.15-2.50). Subanalyses revealed that increased mortality related to HbA(1c) was restricted to hypertensive patients with type 2 diabetes (1.23, 1.04-1.47). Serum triglycerides (by 1 mmol/l) predicted all-cause mortality in women (1.25, 1.06-1.47). CONCLUSIONS: Poor glucose and lipid control and hypertension predicted all-cause mortality. Survival was also predicted by prevalent microalbuminuria and by previous cardiovascular disease. Confirming results from clinical trials, this population-based study has implications for primary and secondary prevention.     

A computer simulation model of diabetes progression, quality of life, and cost

OBJECTIVE: To develop and validate a comprehensive computer simulation model to assess the impact of screening, prevention, and treatment strategies on type 2 diabetes and its complications, comorbidities, quality of life, and cost. RESEARCH DESIGN AND METHODS: The incidence of type 2 diabetes and its complications and comorbidities were derived from population-based epidemiologic studies and randomized, controlled clinical trials. Health utility scores were derived for patients with type 2 diabetes using the Quality of Well Being-Self-Administered. Direct medical costs were derived for managed care patients with type 2 diabetes using paid insurance claims. Monte Carlo techniques were used to implement a semi-Markov model. Performance of the model was assessed using baseline and 4- and 10-year follow-up data from the older-onset diabetic population studied in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). RESULTS: Applying the model to the baseline WESDR population with type 2 diabetes, we predicted mortality to be 51% at 10 years. The prevalences of stroke and myocardial infarction were predicted to be 18 and 19% at 10 years. The prevalences of nonproliferative diabetic retinopathy, proliferative retinopathy, and macular edema were predicted to be 45, 16, and 18%, respectively; the prevalences of microalbuminuria, proteinuria, and end-stage renal disease were predicted to be 19, 39, and 3%, respectively; and the prevalences of clinical neuropathy and amputation were predicted to be 52 and 5%, respectively, at 10 years. Over 10 years, average undiscounted total direct medical costs were estimated to be USD $53,000 per person. Among survivors, the average utility score was estimated to be 0.56 at 10 years. CONCLUSIONS: Our computer simulation model accurately predicted survival and the cardiovascular, microvascular, and neuropathic complications observed in the WESDR cohort with type 2 diabetes over 10 years. The model can be used to predict the progression of diabetes and its complications, comorbidities, quality of life, and cost and to assess the relative effectiveness, cost-effectiveness, and cost-utility of alternative strategies for the prevention and treatment of type 2 diabetes.     

Rapid progression of albumin excretion is an independent predictor of cardiovascular mortality in patients with type 2 diabetes and microalbuminuria.

OBJECTIVE: In patients with type 2 diabetes, microalbuminuria is associated with an increase in predominantly cardiovascular mortality. Considerable interindividual variability in the rate of progression of microalbuminuria exists. The prognostic significance of rate of progression of microalbuminuria with regard to cardiovascular and renal clinical end points is, however, unknown. The purpose of this study was to determine the prognostic significance of rate of progression of microalbuminuria for cardiovascular end points and renal function. RESEARCH DESIGN AND METHODS: In a previous prospective cohort study, progression of microalbuminuria (expressed as mean yearly change in albumin-to-creatinine ratio) was assessed in 58 patients with type 2 diabetes. During a median follow-up of 7 years after progression of microalbuminuria was determined, we registered all-cause mortality and coronary heart disease mortality as primary end points and coronary heart disease (fatal or nonfatal), peripheral vascular disease, ischemic stroke, retinopathy, macroalbuminuria, and change in serum creatinine as secondary end points. RESULTS: Seven subjects died during the study; five of these subjects died of coronary heart disease. Cox's regression analysis identified progression of microalbuminuria as a significant predictor of all-cause mortality (hazard ratio 1.46 per point increase in albumin-to-creatinine ratio per year, P < 0.001), coronary heart disease mortality (hazard ratio 2.32, P = 0.006), and macroalbuminuria (hazard ratio 1.79, P < 0.001). Adjustment for multiple cardiovascular risk factors did not affect these results. Identical analyses for baseline level of microalbuminuria instead of progression rate of microalbuminuria did not show significant hazard ratios. In addition, progression of microalbuminuria significantly predicted an increase in serum creatinine (r = 0.29, P = 0.04). CONCLUSIONS: In patients with type 2 diabetes and microalbuminuria, the rate of progression of albumin excretion seems to be a powerful independent predictor of mortality caused mainly by coronary heart disease.     

A prospective cohort study of predictive value of homocysteine in patients with type 2 diabetes and coronary artery disease

BACKGROUND: Little evidence exists on the role of homocysteine as a predictor of mortality in patients with type 2 diabetes. The aim of this study was to investigate whether elevated plasma homocysteine levels are independently associated with all-cause or cardiovascular mortality in patients with type 2 diabetes and coronary artery disease. METHODS: This is a prospective cohort study that included 507 patients with type 2 diabetes and angiographically proven coronary artery disease. Patients were divided into 2 groups according to homocysteine level above or below median value (12.4 micromol/L): the high homocysteine group (255 patients) and the low homocysteine group (252 patients). The primary end-point of the study was all-cause mortality. RESULTS: There were 103 deaths during a 4-year follow-up: 62 deaths in the high homocysteine group and 41 deaths in the low homocysteine group (Kaplan-Meier estimates of mortality 25.6% and 17.4%, respectively (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.03-2.27, P=0.031). Sixty-two of 103 deaths (60.2%) were of cardiovascular origin: 37 deaths (14.5%) occurred in the high homocysteine group and 25 deaths (9.9%) occurred in the low homocysteine group (P=0.115). Cox proportional hazards model showed that plasma homocysteine was not an independent correlate of all-cause (adjusted hazard ratio [HR] 1.10, 95% CI 0.89-1.33; P=0.397 for 5 micromol/L increase in concentration) or cardiovascular (adjusted HR 1.04, 95% CI 0.80-1.36, P=0.753, for 5 micromol/L increase in concentration) mortality. CONCLUSION: In patients with type 2 diabetes and coronary artery disease, elevated level of homocysteine is an associate of increased cardiovascular risk but not an independent predictor of cardiovascular mortality.     

Adiponectin and leptin concentrations may aid in discriminating disease forms in children and adolescents with type 1 and type 2 diabetes

OBJECTIVE: The incidence of pediatric type 2 diabetes has recently seen an alarming increase. To improve our understanding of pediatric type 2 diabetes and identify markers that discriminate these subjects from those with type 1 diabetes, we performed a multivariant analysis associating serum adiponectin and leptin levels with anthropometrical parameters and disease state. RESEARCH DESIGN AND METHODS: Samples from children and adolescents with type 1 diabetes (n = 41) and type 2 diabetes (n = 17) and from nondiabetic individuals of similar age from the general population (n = 43) were investigated. An analysis included the parameters of matching for BMI and Tanner stage. Receiver-operator characteristic (ROC) curves were established to assess these analytes' association with disease. RESULTS: Contrary to studies of adult type 1 diabetes, adiponectin levels in our pediatric type 1 diabetic subjects (10.2 microg/ml [95% CI 8.6-11.7]) did not differ from those of healthy control subjects (10.6 microg/ml [9.2-12.0]; P = NS). Children with type 2 diabetes (5.5 microg/ml [4.8-6.2]) had significantly lower adiponectin levels than both of those groups. Conversely, type 2 diabetic subjects showed marked elevations in serum leptin concentrations (24.3 ng/ml [17.1-31.5]) compared with healthy control subjects (2.7 ng/ml [1.3-4.1]; P < 0.001) and type 1 diabetic subjects (5.1 ng/ml [3.5-6.7]; P < 0.001). Importantly, each of the properties ascribed to pediatric type 2 diabetes was present when the comparison was restricted to healthy children or type 1 diabetic patients whose BMI was >85th percentile or who had Tanner stage 4 and 5. The evaluation of adiponectin-to-leptin ratios revealed a striking difference between children with type 1 diabetes (6.3 [3.8-8.8]) and type 2 diabetes (0.3 [0.2-0.5]; P < 0.001). CONCLUSIONS: In pediatric diabetes, where diagnosis of disease is often difficult, these studies suggest that the adiponectin-to-leptin ratio may provide additional help in the discrimination between type 1 and type 2 diabetes.     

Age-related macular degeneration in newly diagnosed type 2 diabetic patients and control subjects: a 10-year follow-up on evolution, risk factors, and prognostic significance

OBJECTIVE: To investigate the evolution of visual acuity, age-related macular degeneration (AMD), and its relation to 10-year cardiovascular mortality and risk factors in patients with newly diagnosed type 2 diabetes and control subjects. RESEARCH DESIGN AND METHODS: A 10-year prospective study consisting of a representative group of 133 (70 men, 63 women) newly diagnosed type 2 diabetic patients diagnosed at health centers between 1979 and 1981 and 144 (62 men, 82 women) nondiabetic control subjects recruited from the population register was performed. The frequency of AMD was determined by grading of 45 degrees stereoscopic fundus photographs. The subjects were studied at baseline and after 5 and 10 years. RESULTS: By the 10-year follow-up, visual acuity had declined more markedly in the diabetic patients than in the control subjects. Although the frequency of AMD was nearly the same in both groups (11-19%), it decreased visual acuity earlier in the diabetic patients than in the control group. AMD at baseline predicted 10-year cardiovascular mortality independently of adjustment for other risk factors in the diabetic patients (odds ratio [95% CI] 4.7 [1.1-19.3], P = 0.033). CONCLUSIONS: Visual acuity deteriorated earlier in newly diagnosed type 2 diabetic patients than in the control group although the cross-sectional frequency of AMD was nearly the same in both groups. Interestingly, AMD was an independent risk factor for cardiovascular mortality in type 2 diabetic patients, but the background mechanism(s) behind this association is unknown.     

Lipid and blood pressure treatment goals for type 1 diabetes: 10-year incidence data from the Pittsburgh Epidemiology of Diabetes Complications Study

OBJECTIVE--Subjects with type 1 diabetes are at high risk for many long-term complications, including early mortality and coronary artery disease (CAD). Few data are available on which to base goal levels for two major risk factors, namely blood pressure and lipid/lipoproteins. The objective of this study was to determine at which levels of LDL and HDL cholesterol, triglycerides, and blood pressure the relative risks of type 1 diabetic complications increase significantly. RESEARCH DESIGN AND METHODS--Observational prospective study of 589 patients with childhood-onset type 1 diabetes (<17 years) aged > or =18 years at baseline; 10-year incidence of mortality, CAD, lower-extremity arterial disease, proliferative retinopathy, distal symmetric polyneuropathy, and overt nephropathy. Relative risks were determined using traditional groupings of blood pressure and lipid/lipoproteins, measured at baseline, using the lowest groupings (<100 mg/dl [2.6 mmol/l] LDL cholesterol, <45 mg/dl [1.1 mmol/l] HDL cholesterol, <100 mg/dl [1.1 mmol/l] triglycerides, <110 mmHg systolic blood pressure, and <80 mmHg diastolic blood pressure) as reference. Adjustments for age, sex, and glycemic control were examined. RESULTS--Driven mainly by strong relationships (RR range 1.8-12.1) with mortality, CAD, and overt nephropathy, suggested goal levels are as follows: LDL cholesterol <100 mg/dl (2.6 mmol/l), HDL cholesterol >45 mg/dl (1.1 mmol/l), triglycerides <150 mg/dl (1.7 mmol/l), systolic blood pressure <120 mmHg, and diastolic blood pressure <80 mmHG: Age, sex, and glycemic control had little influence on these goals. CONCLUSIONS--Although observational in nature, these data strongly support the case for vigorous control of lipid levels and blood pressure in patients with type 1 diabetes.     

Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study.

OBJECTIVE: This population-based study, carried out in the framework of the Verona Diabetes Study, investigated mortality from specific causes in known type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A cohort of 7,148 known type 2 diabetic patients (3,366 men and 3,782 women) was identified on 31 December 1986 and followed up for 5 years (1987-1991). Underlying causes of death were obtained from death certificates and were coded according to the International Classification of Diseases, Ninth Revision. Cause-specific death rates of diabetic subjects were compared with those of the inhabitants of Verona. By 31 December 1991, 1,550 diabetic subjects (744 men and 806 women) had died. RESULTS: The standardized mortality ratio (SMR) for all causes of death was 1.42 (95% CI 1.35-1.50). The highest SMRs were for the following specific causes: diabetes (SMR 4.47 [3.91-5.10]), gastrointestinal diseases (1.83 [1.50-2.21])--particularly liver cirrhosis (2.52 [1.96-3.20])--and cardiovascular diseases (1.34 [1.23-1.44]), particularly cerebrovascular (1.48 [1.25-1.73]) and ischemic heart diseases (1.41 [1.24-1.62]). A significantly higher than expected risk of mortality for cardiovascular causes was already present in the first 5 years after diagnosis and decreased with age. Type 2 diabetic patients treated with insulin had a higher risk of dying than those treated orally or by diet. CONCLUSIONS: The highest SMRs in the diabetic cohort were for diabetes and liver cirrhosis. The mortality risk for cardiovascular diseases, although significantly higher than expected, was much lower in Italian type 2 diabetic patients than that reported for American patients. The evidence of an early effect on mortality suggests that prevention, early diagnosis, and treatment should be improved.     

Timing is everything: age of onset influences long-term retinopathy risk in type 2 diabetes, independent of traditional risk factors

OBJECTIVE—To test the hypothesis that age of type 2 diabetes onset influences inherent susceptibility to diabetic retinopathy, independent of disease duration and degree of hyperglycemia.RESEARCH DESIGN AND METHODS—Retinopathy data from 624 patients with a type 2 diabetes duration of 20–30 years (group A) were analyzed by stratifying patients according to age of onset of diabetes and glycemic control. Retinopathy status was scored clinically as per a modified Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. To obviate possible bias due to a higher attrition from comorbidities in those with later-onset diabetes and retinopathy, 852 patients with type 2 diabetes of shorter duration (10–12 years, group B) were similarly studied.RESULTS—Prevalence and severity of retinopathy was significantly higher in the younger-onset, group A patients. When further stratified according to mean A1C, retinopathy risk remained increased in younger-onset patients. The greatest impact was seen in those with a mean A1C >9% (odds ratio [OR] for retinopathy 16.6, 7.5, and 2.7 for age of diagnosis <45, 45–55, and >55 years, respectively, P = 0.003). By logistic regression, earlier type 2 diabetes onset is associated with increased retinopathy risk, independent of traditional risk factors (OR of retinopathy 1.9, 1.1, and 1 for age of onset <45, 45–55, and >55 years, respectively). Similar results were found in group B patients.CONCLUSIONS— These data suggest an increased inherent susceptibility to diabetic retinopathy with earlier-onset type 2 diabetes. This further supports the importance of delaying development of diabetes and also implies a need for more stringent metabolic targets for younger individuals.Superimposed on the worldwide epidemic of diabetes that we are currently facing is the demographic trend to an ever younger age of diagnosis of type 2 diabetes (1). In recent studies, type 2 diabetes constitutes up to 45% of incident pediatric diabetes, and 7–22% of adolescent diabetes presents with diabetes-specific complications at diagnosis (2,3). To date, few studies have examined long-term outcomes as a function of age of diagnosis in type 2 diabetes, and even fewer have looked at the development of retinopathy specifically. There is some limited data suggesting that young-onset diabetes is associated with an increased risk for complications compared with later-onset diabetes (4) and that the development and progression of complications might be particularly rapid in early-onset disease (2). What is hitherto unknown is whether the increased prevalence of complications associated with early-onset disease is simply a consequence of the longer duration of disease, a consequence of a more severe metabolic phenotype, or in fact something specific to the diabetic milieu in younger patients that makes tissues more inherently susceptible to hyperglycemic damage.We therefore explore the hypothesis that in type 2 diabetes, susceptibility to retinopathy is dependent on age of diabetes onset. The isolated effect of age of diabetes onset on long-term retinopathy status was examined independent of duration of diabetes and glycemic control, the two most important risk factors for retinopathy.     

High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes

OBJECTIVE

To determine whether immunocomplexes (ICs) containing advanced glycation end product (AGE)–LDL (AGE-LDL) and oxidized LDL (oxLDL) contribute to the development of retinopathy over a 16-year period in subjects with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Levels of AGE-LDL and oxLDL in ICs were measured in 517 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Retinopathy was assessed by stereoscopic fundus photography. Cox proportional hazards models were used to assess the effect of AGE-LDL-ICs and oxLDL-ICs on retinopathy progression.

RESULTS

In unadjusted models, higher baseline levels of AGE-LDL-ICs and oxLDL-ICs significantly predicted progression of diabetic retinopathy outcomes. After adjustment by study-design variables (treatment group, retinopathy cohort, duration of type 1 diabetes, and baseline albumin excretion rate [AER], hemoglobin A_1c (HbA_1c), and Early Treatment Diabetic Retinopathy Study [ETDRS] score), one SD increase in IC levels was associated with 47% (hazard ratio [HR] 1.47 [95% CI 1.19–1.81]; AGE-LDL-IC) and 45% (1.45 [1.17–1.80]; oxLDL-IC) increased risk of developing proliferative diabetic retinopathy (PDR) and 37% (1.37 [1.12–1.66]; to both ICs) increased risk of progressing to severe nonproliferative retinopathy. Analyses were stratified by retinopathy cohort because results differed between primary and secondary cohorts. For AGE-LDL-ICs, HR for progression to PDR was 2.38 (95% CI 1.30–4.34) in the primary cohort and attenuated in the secondary cohort (1.29 [1.03–1.62]). Similar results were observed for oxLDL-ICs.

CONCLUSIONS

Increased levels of AGE-LDL and oxLDL in ICs are associated with increased risk for progression to advanced retinopathy in patients with type 1 diabetes, indicating that the antibody response to modified LDL plays a significant role in retinopathy progression.Diabetic retinopathy is a major cause of vision loss in working-age adults (1) and affects the majority of people with type 1 diabetes at some stage of their lives (2). Established risk factors are long duration of diabetes, poor glycemic control, hypertension, dyslipidemia, smoking, and diabetic renal disease (3). In spite of this knowledge, diabetic retinopathy still occurs at an unacceptably high rate (4). Identification of novel markers and mechanisms for its onset and progression will facilitate new preventive and therapeutic strategies.In people both with and without diabetes, conventional “quantitative” measures of dyslipidemia (e.g., high LDL cholesterol or low HDL cholesterol) are associated with increased risk for atherosclerosis (5). Among subjects with diabetes, conventional lipid profiles are also associated with microvascular complications, including diabetic retinopathy (4). However the associations of plasma lipoprotein levels with diabetic retinopathy are less pronounced than for atherosclerosis, likely because in the retina specialized barrier functions must break down before lipoprotein-mediated effects become operative (6).In recent years, the importance of lipoprotein modification in the propagation of vascular damage has been recognized (7). Modifications including glycation, oxidation, and formation of advanced glycation end products (AGEs) are observed predominantly in extravasated lipoproteins and are enhanced in diabetes. These lipoprotein modifications are sufficient to elicit the synthesis of auto-antibodies that, in turn, lead to the formation of immunocomplexes (ICs) (8).Previous studies have focused on the effects of modified lipoproteins on atherosclerosis, but we have demonstrated that similar principles apply in diabetic retinopathy (6). Normally, the inner and outer blood retinal barriers prevent any extravasation of plasma lipoproteins, a special property of the retina; however, in diabetes, damage to these barriers enables extravasation and subsequent lipoprotein modification. High levels of modified forms of LDL in circulating ICs have been implicated as risk factors for atherosclerosis (9), but few studies have examined their associations with diabetic retinopathy. In this study, we have examined progression of retinopathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort of patients with type 1 diabetes, and we report a significant relationship between circulating levels of ICs containing AGE-LDL and oxidized LDL (oxLDL) and progression of diabetic retinopathy over a 16-year period.