A nonparametric relative treatment effect for direct comparisons of censored paired survival outcomes.

A frequently addressed issue in clinical trials is the comparison of censored paired survival outcomes, for example, when individuals were matched based on their characteristics prior to the analysis. In this regard, a proper incorporation of the dependence structure of the paired censored outcomes is required and, up to now, appropriate methods are only rarely available in the literature. Moreover, existing methods are not motivated by the strive for insights by means of an easy-to-interpret parameter. Hence, we seek to develop a new estimand-driven method to compare the effectiveness of two treatments in the context of right-censored survival data with matched pairs. With the help of competing risks techniques, the so-called relative treatment effect is estimated. This estimand describes the probability that individuals under Treatment 1 have a longer lifetime than comparable individuals under Treatment 2. We derive hypothesis tests and confidence intervals based on a studentized version of the estimator, where resampling-based inference is established by means of a randomization method. In a simulation study, we demonstrate for numerous sample sizes and different amounts of censoring that the developed test exhibits a good power. Finally, we apply the methodology to a well-known benchmark data set from a trial with patients suffering from diabetic retinopathy.

Investigation of the Systemic Immune Inflammation (SII) Index as an Indicator of Morbidity and Mortality in Type 2 Diabetic Retinopathy Patients in a 4-Year Follow-Up Period.

Background and Objectives: This study aimed to investigate the relationship between the systemic immune inflammation (SII) index and the development of micro and macro complications and mortality within the first year and the following three years in type 2 diabetic retinopathy patients. Materials and Methods: The retrospective study included 523 type 2 diabetic retinopathy patients seen in the endocrinology outpatient clinic of our hospital between January and December 2019. Their demographic and clinical characteristics were analyzed using descriptive statistics. The normal distribution of quantitative data was assessed by the Shapiro-Wilk test. Mann-Whitney U, McNemar-Chi-square, and Cochran's Q tests were used to analyze the SII values and complication rates over time. An ROC analysis determined the sensitivity and specificity of SII. A multiple linear regression analysis examined the relationship between variables and SII, while Spearman's test assessed the correlation between CRP and SII. p < 0.05 was accepted as significant. Results: The mean age of patients was 63.5 ± 9.3 years, with mean SII values of 821.4 ± 1010.8. Higher SII values were significantly associated with acute-chronic renal failure, peripheral arterial disease, and hospitalization rates in both the first year and the following three years (p < 0.05 for all). Significant cut-off values for SII were found for micro- and macrovascular complications and death within the first year (p < 0.05 for all). The ROC curve analysis identified an optimal SII cut-off value of >594.0 for predicting near-term (1-year) complications and mortality, with a sensitivity of 73.8% and specificity of 49.4% (area under the ROC curve: 0.629, p = 0.001). Multiple linear regression indicated that smoking of at least 20 pack-years had a significant positive effect on SII. The Spearman test showed a weak positive correlation between SII and CRP. Conclusions: High SII values predict both early and late acute-chronic renal failure, peripheral arterial disease, and hospitalizations in patients with type 2 diabetic retinopathy. The study also shows that high SII values may predict microvascular and macrovascular complications of type 2 DM and mortality risk in the early period in patients with type 2 diabetic retinopathy. In addition, comorbidities and inflammatory habits, such as long-term smoking, should be considered in the clinical use of SII.

Do Black and Asian individuals wait longer for treatment? A survival analysis investigating the effect of ethnicity on time-to-clinic and time-to-treatment for diabetic eye disease.

AIMS/HYPOTHESIS: This study explored the impact of ethnicity on time-to-clinic, time-to-treatment and rates of vision loss in people referred to hospital with diabetic eye disease. METHODS: A survival analysis was performed on all referrals from an inner-city diabetic eye screening programme to a tertiary hospital eye service between 1 October 2013 and 31 December 2017. Exclusion criteria were failure to attend hospital, distance visual acuity in both eyes too low to quantify with the Early Treatment Diabetic Retinopathy Study (ETDRS) letter chart and treatment received prior to referral. Demographic and screening grade data were collected at the point of referral. Small-area statistics and census data were used to calculate indices of multiple deprivation. The main outcome measures were time taken from the date of referral for an individual to achieve the following: (1) attend the first hospital clinic appointment; (2) receive the first macular laser, intravitreal anti-vascular endothelial growth factor injection or pan-retinal photocoagulation treatment, in either eye; and (3) lose at least ten ETDRS letters of distance visual acuity, in either eye. RESULTS: Of 2062 referrals, 1676 individuals were included. Mean age (± SD) was 57.6 ± 14.7 years, with 52% male sex and 86% with type 2 diabetes. The ethnicity profile was 52% Black, 30% White, 10% Asian and 9% mixed/other, with similar disease severity at the time of referral. Time-to-clinic was significantly longer for Asian people than for Black people (p = 0.03) or White people (p = 0.001). Time-to-treatment was significantly longer for Black people than for White people (p = 0.02). Social deprivation did not significantly influence time-to-treatment. There were no significant differences in the rates of vision loss between ethnic groups. CONCLUSIONS/INTERPRETATION: Black people wait longer for hospital eye treatment compared with their White counterparts. The reasons for this delay in treatment warrant further investigation.

Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease.

BACKGROUND: Multiple modifiable risk factors for late complications in patients with diabetic kidney disease (DKD), including hyperglycemia, hypertension and dyslipidemia, increase the risk of a poor outcome. DKD is associated with a very high cardiovascular risk, which requires simultaneous treatment of these risk factors by implementing an intensified multifactorial treatment approach. However, the efficacy of a multifactorial intervention on major fatal/non-fatal cardiovascular events (MACEs) in DKD patients has been poorly investigated. METHODS: Nephropathy in Diabetes type 2 (NID-2) study is a multicentre, cluster-randomized, open-label clinical trial enrolling 395 DKD patients with albuminuria, diabetic retinopathy (DR) and negative history of CV events in 14 Italian diabetology clinics. Centres were randomly assigned to either Standard-of-Care (SoC) (n = 188) or multifactorial intensive therapy (MT, n = 207) of main cardiovascular risk factors (blood pressure < 130/80 mmHg, glycated haemoglobin < 7%, LDL, HDL and total cholesterol < 100 mg/dL, > 40/50 mg/dL for men/women and < 175 mg/dL, respectively). Primary endpoint was MACEs occurrence by end of follow-up phase. Secondary endpoints included single components of primary endpoint and all-cause death. RESULTS: At the end of intervention period (median 3.84 and 3.40 years in MT and SoC group, respectively), targets achievement was significantly higher in MT. During 13.0 years (IQR 12.4-13.3) of follow-up, 262 MACEs were recorded (116 in MT vs. 146 in SoC). The adjusted Cox shared-frailty model demonstrated 53% lower risk of MACEs in MT arm (adjusted HR 0.47, 95%CI 0.30-0.74, P = 0.001). Similarly, all-cause death risk was 47% lower (adjusted HR 0.53, 95%CI 0.29-0.93, P = 0.027). CONCLUSION: MT induces a remarkable benefit on the risk of MACEs and mortality in high-risk DKD patients. Clinical Trial Registration ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925.

Importance of hematological parameters for micro- and macrovascular outcomes in patients with type 2 diabetes: the Rio de Janeiro type 2 diabetes cohort study.

BACKGROUND: The prognostic importance of several hematological parameters has been scarcely investigated in type 2 diabetes. So, we aimed to evaluate their prognostic importance for development of complications in a cohort of type 2 diabetes. METHODS: In a prospective study, 689 individuals with type 2 diabetes had blood red cell, platelet and leukocyte parameters obtained at baseline. Multivariate Cox analyses examined the associations between several hematological parameters (including neutrophyl-to-lymphocyte, lymphocyte-to-monocyte, platelet-to-lymphocyte, and monocyte-to-HDL ratios) and the occurrence of microvascular (retina, renal and peripheral neuropathy) and cardiovascular complications (total cardiovascular events [CVEs], and major adverse CVEs [MACEs]), and all-cause and cardiovascular mortality. Improvements in risk discrimination were assessed by C-statistics and Integrated Discrimination Improvement (IDI) index. RESULTS: During a median follow-up of 10.5 years, 212 patients had a CVE (174 MACEs), 264 patients died (131 cardiovascular deaths); 206 had a renal, 161 a retinopathy and 179 patients had a neuropathy outcome. In multivariate-adjusted analyses, the lymphocytes count and lymphocyte-to-monocyte ratio were protective (hazard ratios [HRs]: 0.77 and 0.72, respectively), whereas the neutrophyl-to-lymphocyte and platelet-to-lymphocyte ratios were associated with increased risks (HRs: 1.19 and 1.17) for all-cause mortality. For cardiovascular mortality, the monocytes count, the neutrophyl-to-lymphocyte and monocyte-to-HDL ratios were associated with increased risks and the lymphocyte-to-monocyte ratio was protective. Higher lymphocyte-to-monocyte ratio was protective for renal failure outcome. However, none of them improved risk discrimination. CONCLUSIONS: Low lymphocytes count and leukocyte ratios that mainly included lymphocytes were predictors of macrovascular complications and mortality in individuals with type 2 diabetes. However, they did not improve risk prediction over traditional risk factors.

Retinopathy predicts stroke but not myocardial infarction in type 2 diabetes: the Fremantle Diabetes Study Phase II.

BACKGROUND: Microangiopathy in type 2 diabetes (T2D) is associated with cardiovascular disease (CVD), but most relevant studies were performed > 10 years ago. CVD risk factor management has since improved. The aim of this study was to determine whether diabetic retinopathy (DR) and its severity increases stroke and myocardial infarction (MI) risk in a contemporary cohort. METHODS: Fremantle Diabetes Study Phase II participants with T2D had DR graded from fundus photography at baseline between 2008 and 2011. Subsequent hospitalizations and mortality for MI or stroke were ascertained through validated data linkage to end-2016. Cox regression modelling identified predictors of first stroke and MI including DR presence and severity. RESULTS: The 1521 participants with T2D and known DR status (mean age 65.6 years, 52.1% males, median diabetes duration 9.0 years) were followed for a mean of 6.6 years. After excluding those with prior MI/stroke, there were 126 incident MIs among 1393 eligible participants and 53 incident strokes in 1473 eligible participants, respectively. Moderate non-proliferative DR (NPDR) or worse was significantly and independently associated with an increased risk of incident stroke (adjusted hazard ratio 2.55 (95% CI 1.19, 5.47), p = 0.016). Retinopathy presence and severity increased the risk of incident MI in unadjusted models (p ≤ 0.001), but these associations were no longer statistically significant after adjusting for other risk factors. CONCLUSIONS: Moderate NPDR or worse was associated with an increased risk of first stroke in Australians with T2D. Intensified CVD risk factor management should be considered for patients with at least moderate NPDR.

Diabetic retinopathy predicts cardiovascular mortality in diabetes: a meta-analysis.

BACKGROUND: The prognostic significance of diabetic retinopathy (DR) for cardiovascular diseases (CVD) remained unclear. Therefore, we performed this meta-analysis to assess whether DR predicted CVD mortality in diabetic patients. METHODS: We searched PubMed, Embase, Web of Science and Cochrane Library for cohort studies reporting the association of DR and CVD mortality. Then we pooled the data for analysis. RESULTS: After screening the literature, 10 eligible studies with 11,239 diabetic subjects were finally included in quantitative synthesis. The pooled risk ratio (RR) of DR, mild DR, and severe DR for CVD mortality was 1.83 (95% confidence interval (CI): 1.42, 2.36; p < 0.001), 1.13 (95% CI 0.81, 1.59; p = 0.46), and 2.26 (1.31, 3.91; p = 0.003), respectively, compared to those without DR. In type 2 DM, the patients with DR had a significantly higher CVD mortality (RR: 1.69; 95% CI 1.27, 2.24; p < 0.001). Subgroup analysis also showed a significantly higher CVD mortality in DR according to various regions, study design, data source, and follow-up period (all RR > 1; all P values < 0.05). Data from 2 studies showed no significant correlation of DR and CVD mortality in diabetic patients receiving cardiovascular surgery (RR: 2.40; 95% CI 0.63, 9.18; P = 0.200). CONCLUSIONS: DR is a risk marker of cardiovascular death, and severe DR predicts a doubled mortality of CVD in diabetes. These findings indicate the importance of early identification and management of diabetic patients with DR to reduce the risk of death.

Effect of duration and burden of microvascular complications on mortality rate in type 1 diabetes: an observational clinical cohort study.

AIMS/HYPOTHESIS: The role of burden and duration of multiple microvascular complications on mortality rate has not been explored in detail in type 1 diabetes. Taking complication burden and time-updated duration into account we aimed to quantify mortality rate in individuals with and without microvascular complications. METHODS: This observational clinical cohort included 3828 individuals with type 1 diabetes attending the Steno Diabetes Center Copenhagen in 2001-2013. We used information on mortality and detailed clinical measures of microvascular complications from electronic patient records. Poisson models were used to model mortality rates according to complication burden. RESULTS: During 26,665 person-years of follow-up, 503 deaths occurred. Compared with individuals without microvascular complications, the mortality rate ratio was 2.20 (95% CI 1.79, 2.69) for individuals with diabetic kidney disease, 1.72 (95% CI 1.39, 2.12) for individuals with neuropathy and 1.02 (95% CI 0.77, 1.37) for individuals with retinopathy, all adjusted for calendar time (year/month/day), age, duration of diabetes, sex, HbA1c, LDL-cholesterol, BMI, smoking status, systolic blood pressure, use of antihypertensive and lipid-lowering medication, and cardiovascular disease status. In individuals with two complications or more, the risk of mortality did not exceed the combined risk from each individual complication. Mortality rate ratios increased immediately after diagnosis of neuropathy and diabetic kidney disease. Mortality rate ratios were independent of the duration of neuropathy and retinopathy, while the mortality rate associated with diabetic kidney disease reached a stable level after approximately 3 years. CONCLUSIONS/INTERPRETATION: Neuropathy and diabetic kidney disease are strong and independent risk markers of mortality in type 1 diabetes, whereas no evidence of higher mortality rate was found for retinopathy. We found no indication that the mortality risk with multiple complications exceeds the risk conferred by each complication separately. The duration spent with microvascular complications had only a marginal effect on mortality.

Microvascular complications burden (nephropathy, retinopathy and peripheral polyneuropathy) affects risk of major vascular events and all-cause mortality in type 1 diabetes: a 10-year follow-up study.

BACKGROUND: Microvascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes. METHODS: We recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis. RESULTS: Out of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59-7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65-15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42-94.57], p < 0.0001). After adjustments, HRs were: 1 MC 2.05 (95% CI 0.88-4.76), 2 MC 1.98 (95% CI 0.75-5.21), 3 MC 7.02 (95% CI 2.44-20.20, p = 0.002). Forty-nine subjects (6.7%) had at least one cardiovascular event, and cumulative incidence went from no-MC 2.2% (Ref) to 1 MC 5.0%; (HR 2.27 [95% CI 0.96-5.38]), 2 MC 26.8% (HR 12.88 [95% CI 5.82-28.50]) and 3 MC 40.9% (HR 29.34 [95% CI 11.59-74.25], p < 0.0001). Upon adjustments, HRs were: 1 MC 1.59 (95% CI 0.65-3.88), 2 MC 4.33 (95% CI 1.75-10.74), 3 MC 9.31 (95% CI 3.18-27.25, p < 0.0001). Thirty-five individuals (4.8%) had at least one coronary event, which cumulative incidence increased with MC burden (p < 0.0001). CONCLUSIONS: In type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.

Impact of model misspecification in shared frailty survival models.

Survival models incorporating random effects to account for unmeasured heterogeneity are being increasingly used in biostatistical and applied research. Specifically, unmeasured covariates whose lack of inclusion in the model would lead to biased, inefficient results are commonly modeled by including a subject-specific (or cluster-specific) frailty term that follows a given distribution (eg, gamma or lognormal). Despite that, in the context of parametric frailty models, little is known about the impact of misspecifying the baseline hazard or the frailty distribution or both. Therefore, our aim is to quantify the impact of such misspecification in a wide variety of clinically plausible scenarios via Monte Carlo simulation, using open-source software readily available to applied researchers. We generate clustered survival data assuming various baseline hazard functions, including mixture distributions with turning points, and assess the impact of sample size, variance of the frailty, baseline hazard function, and frailty distribution. Models compared include standard parametric distributions and more flexible spline-based approaches; we also included semiparametric Cox models. The resulting bias can be clinically relevant. In conclusion, we highlight the importance of fitting models that are flexible enough and the importance of assessing model fit. We illustrate our conclusions with two applications using data on diabetic retinopathy and bladder cancer. Our results show the importance of assessing model fit with respect to the baseline hazard function and the distribution of the frailty: misspecifying the former leads to biased relative and absolute risk estimates, whereas misspecifying the latter affects absolute risk estimates and measures of heterogeneity.

Presence of diabetic retinopathy is associated with worse 10-year mortality among Indigenous Australians in Central Australia: The Central Australian ocular health study.

IMPORTANCE: Diabetes mellitus (DM) is highly prevalent among Indigenous Australians and contributes greatly to premature death. The association of diabetic retinopathy (DR) with early mortality, however, has not previously been reported among Indigenous Australians. BACKGROUND: To investigate associations between 10-y mortality and the presence of DR among Indigenous Australians living in Central Australia. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 1257 individuals aged 40 y or older, living in one of 30 remote communities within Central Australia were recruited through outreach clinics. METHODS: Fundus examination was performed on all patients at recruitment. The presence of any DR was recorded. MAIN OUTCOME MEASURES: Mortality rate and cause were obtained at 10 y, and their association with any DR was determined. RESULTS: Ten-year all-cause mortality was found to be 29.3%. Of those with DM but no DR, 24.0% died during the 10 y after recruitment, compared with 40.1% for those with any DR (P < 0.0001). Those who had any DR were 75% more likely to die (hazard ratio [HR] 1.75; P < 0.0001) and were more likely to die from renal failure (HR 2.71; P = 0.004) or stroke (HR 5.91; P = 0.026). CONCLUSION AND RELEVANCE: The presence of any DR among those with DM, was associated with a 75% greater 10-y all-cause mortality rate and were more likely to die from renal failure or stroke. We recommend that whenever DR is noted among Indigenous Australians with DM, that they be immediately referred for investigation and management of risk factors, which might predispose to renal failure and stroke.

Long-term survival rates of patients undergoing vitrectomy for diabetic retinopathy in an Australian population: a population-based audit.

IMPORTANCE: Five-year survival rates in patients undergoing vitrectomy for diabetic retinopathy (DR) vary from 68% to 95%. No study has been conducted in an Australian population. BACKGROUND: We aimed to determine the survival rates of patients undergoing diabetic vitrectomy in an Australian population. DESIGN: Retrospective audit, tertiary centre hospitals and private practices. PARTICIPANTS: All individuals in South Australia and the Northern Territory who underwent their first vitrectomy for diabetic complications between January 1, 2007 and December 31, 2011. METHODS: An audit of all eligible participants has been completed previously. Survival status as of July 6, 2018 and cause of death were obtained using SA/NT DataLink. Kaplan-Meier survival curves and multivariate cox-regressions were used to analyse survival rates and identify risk factors for mortality. MAIN OUTCOME MEASURES: Five-, seven- and nine-year survival rates. RESULTS: The 5-, 7- and 9-year survival rates were 84.4%, 77.9% and 74.7%, respectively. The most common cause of death was cardiovascular disease. Associated with increased mortality independent of age were Indigenous ethnicity (HR = 2.04, 95% confidence interval [CI]: 1.17-3.57, P = 0.012), chronic renal failure (HR = 1.76, 95% CI: 1.07-2.89, P = 0.026) and renal failure requiring dialysis (HR = 2.32, 95% CI: 1.25-4.32, P = 0.008). CONCLUSIONS AND RELEVANCE: Long-term survival rates after diabetic vitrectomy in Australia are similar to rates reported in other populations. Indigenous ethnicity and chronic renal failure were the most significant factors associated with long-term mortality. This information can guide allocation of future resources to improve the prognosis of these high risk groups.

Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial.

AIMS/HYPOTHESES: We aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes. METHODS: We performed a case-cohort study (N = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid. RESULTS: In models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p < 0.001) and microvascular events (continuous NRI +14.4%, p = 0.012). CONCLUSIONS/INTERPRETATION: We report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.

Clinical impact of coexisting retinopathy and vascular calcification on chronic kidney disease progression and cardiovascular events.

BACKGROUND AND AIMS: Retinopathy and vascular calcification (VC) are representative markers of microvascular and macrovascular dysfunction in patients with chronic kidney disease (CKD). However, their relationship and combined effects on clinical outcomes remain undetermined. METHODS AND RESULTS: We included 523 patients with nondialysis-dependent CKD stage 3-5 who had been examined with fundus photography for diabetic or hypertensive retinopathy. Simple radiographs were analyzed for the presence of VC. The clinical significance of VC of the abdominal aorta and iliofemoral artery (apVC) and retinopathy was evaluated in terms of the rate of renal function decline and composite of any cardiovascular event or death. CKD patients with retinopathy showed higher prevalence of apVC than those without retinopathy (25.6% vs. 12.5%, P < 0.001).The presence of retinopathy was independently associated with apVC (OR 2.13, 95% CI 1.31, 3.49). In multivariate analysis, compared with subjects with neither apVC nor retinopathy, the coexistence of both apVC and retinopathy were independently associated with rapid renal function decline (ß = -1.51; 95% CI -2.40, -0.61), whereas apVC or retinopathy alone were not. Compared with subjects with neither apVC nor retinopathy, the HRs for composite end points were 1.05 (95% CI 0.48, 2.27), 1.79 (95% CI 1.14, 2.80), and 2.07 (95% CI 1.17, 3.67) for patients with apVC only, those with retinopathy only, and those with both apVC and retinopathy, respectively. CONCLUSION: The coexistence of VC and retinopathy was independently associated with CKD progression and cardiovascular events or deaths, and its combined effect was stronger than any separate condition.

Prospective Association between Diabetic Retinopathy and Cardiovascular Disease-A Systematic Review and Meta-analysis of Cohort Studies.

BACKGROUND: Diabetic retinopathy (DR) is linked to increased risk of cardiovascular (CV) disease. However, the effect size of the association was not consistent. In this study, we performed a systematic review and meta-analysis of available cohort studies to determine the association between DR and CV disease, and to investigate the factors that influence the association. METHODS: Terms related to DR and CV disease were searched from MEDLINE and EMBASE database. High-quality articles (Newcastle-Ottawa scales above 6) conducted in cohort studies reporting the association between DR and CV disease were identified. Study-specific estimates were pooled using random effects with inverse variance meta-analysis. Subgroup analysis was performed according to diabetes types. Heterogeneity of included studies was assessed using the I(2) test. The cause of the heterogeneity was examined using metaregression analyses. RESULTS: A total of 13 studies representing 17,611 patients without CV disease at baseline were included. At follow-up, there were 1457 CV disease-related incidences. Overall, DR was associated with increased risk of CV disease (relative risk [RR]: 2.42, 95% confidence interval [CI]: 1.77-3.31) in diabetes. Specifically, the RR was 3.59 (95% CI: 1.79-7.20) for type 1 diabetes and 1.81 (95% CI: 1.47-2.23) for type 2 diabetes. Significant heterogeneity was found in studies with type 1 diabetes. Metaregression analysis showed that baseline systolic blood pressure was a key factor leading to the heterogeneity. CONCLUSION: In conclusion, DR is significantly associated with CV disease incidence and CV disease-related mortality in diabetes. Patients with DR may need more intensive management to control future CV disease attacks.

C-peptide concentration, mortality and vascular complications in people with Type 2 diabetes. The Skaraborg Diabetes Register.

AIM: To study the prognosis of patients with newly diagnosed Type 2 diabetes in primary care in relation to their baseline C-peptide concentration. METHODS: C-peptide concentrations were determined in 399 patients aged < 65 years with newly diagnosed Type 2 diabetes using the Skaraborg Diabetes Register, Sweden. Data on cardiovascular complications and death were extracted from national registers and a local study of retinopathy. Statistical analyses were performed using Cox regression. RESULTS: An analysis of C-peptide concentrations in quartiles, after adjusting for confounders, showed that patients in the highest quartile had a 2.75-fold higher risk of death from all causes compared with those in the lowest quartile (CI 1.17-6.47). By contrast, C-peptide concentration was not associated with the incidence of cardiovascular events or the development of retinopathy. CONCLUSIONS: Measurement of C-peptide concentration at diagnosis could help identify patients who are at high risk and who presumably would benefit from more intensive treatment.

Association of diabetic retinopathy on all-cause and cause-specific mortality in older adults with diabetes: National Health and Nutrition Examination Survey, 2005-2008.

To evaluate the effect of diabetic retinopathy (DR) status or severity on all-cause and cause-specific mortality among diabetic older adults in the United States using the most recent National Health and Nutrition Examination Survey (NHANES) follow-up mortality data. The severity of DR was graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) grading scale. Multiple covariate-adjusted Cox proportional hazards regression models, Fine and Gray competing risk regression models, and propensity score matching (PSM) methods were used to assess the risk of all-cause and cause-specific mortality in individuals with diabetes. All analyses adopted the weighted data and complex stratified design approach proposed by the NHANES guidelines. Time to death was calculated based on the time between baseline and date of death or December 31, 2019, whichever came first. Ultimately 1077 participants, representing 3,025,316 US non-hospitalized individuals with diabetes, were included in the final analysis. After a median follow-up of 12.24 years (IQR, 11.16-13.49), 379 participants were considered deceased from all-causes, with 43.90% suffering from DR, including mild DR (41.50%), moderate to severe DR (46.77%), and proliferative DR (PDR) (67.21%). DR was associated with increased all-cause, cardiovascular disease (CVD) and diabetes mellitus (DM)-specific mortality, which remained consistent after propensity score matching (PSM). Results of DR grading assessment suggested that the presence of mild, moderate to severe NPDR was significantly associated with increased risk of all-cause and CVD-specific mortality, while the presence and severity of any DR was associated with increased DM-specific mortality, with a positive trend. The presence of DR in elderly individuals with diabetes is significantly associated with the elevated all-cause and CVD mortality. The grading or severity of DR may reflect the severity of cardiovascular disease status and overall mortality risk in patients with diabetes.

Transition probabilities of diabetic retinopathy and death in an Asian population with diabetes.

PURPOSE: To evaluate the dynamic transitions in diabetic retinopathy (DR) severity over time and associated risk factors in an Asian population with diabetes. DESIGN: Longitudinal cohort study METHODS: We analyzed data from 9481 adults in the Singapore Integrated Diabetic Retinopathy Screening Program (2010-2015) with linkage to death registry. A multistate Markov model adjusted for age, sex, systolic blood pressure (SBP), diabetes duration, HbA1c, and body mass index (BMI) was applied to estimate annual transition probabilities between four DR states (no, mild, moderate, and severe/proliferative) and death, and the mean sojourn time in each state. RESULTS: The median assessment interval was 12 months, with most patients having 3 assessments. Annual probabilities for DR progression (no-to-mild, mild-to-moderate and moderate-to-severe/proliferative) were 6.1 %, 7.0 % and 19.3 %, respectively; and for regression (mild-to-no, moderate-to-mild and severe-to-moderate) were 55.4 %, 17.3 % and 4.4 %, respectively. Annual mortality rates from each DR state were 1.2 %, 2.0 %, 18.7 %, and 30.0 %. The sojourn time in each state were 8.2, 0.8, 0.8 and 2.2 years. Higher HbA1c and SBP levels were associated with progression of no-mild and mild-moderate DR, and diabetes duration with no-to-mild and moderate-to-severe/proliferative DR. Lower HbA1c levels were associated with regression from mild-to-no and moderate-to-mild, and higher BMI with mild-to-no DR. CONCLUSIONS: Our results suggest a prolonged duration (∼8 years) in developing mild DR, with faster transitions (within a year) from mild or moderate states. Moderate/above DR greatly increases the probability of progression and death as compared to mild DR/below. HbA1c was associated with both progression as well as regression.

Prevalence, incidence and mortality of diagnosed diabetes: evidence from an Italian population-based study.

AIMS: To describe trends in diagnosed diabetes prevalence, incidence and mortality from 2000 to 2007 in the most heavily populated Italian region. METHODS: We examined the prevalence and incidence rates of Type 1 and Type 2 diabetes and yearly mortality rates among individuals with diabetes from 2000 to 2007 using an administrative health database of prescription, disease-specific exemption and hospitalization records of more than 9 million inhabitants of Lombardy. Age- and sex-specific rates were calculated and temporal trends for subjects aged ≥ 30 years were analysed. RESULTS: The crude point diabetes prevalence rose from 3.0% in 2000 to 4.2% in 2007, a 40% increase. The incidence remained stable during the study period with a rate of 4/1000 per year. Overall mortality declined from 43.2/1000 in 2001 to 40.3/1000 in 2007 (6.7% decrease) at a rate slightly higher than that of the general population (4.8% decrease). Our projection in subjects aged ≥ 30 years indicates that the prevalence will rise continuously over the next years, reaching 11.1% in 2030. CONCLUSIONS: The prevalence of diabetes increased substantially between 2000 and 2007, mainly because there are more patients with a new diagnosis each year than those who die. The increase observed by 2007 almost reached the World Health Organization prediction for 2030. Our analyses suggest that the increase will continue over the next few decades. These data are important for defining the burden of diabetes in the near future, to help in planning health services and ensure proper allocation of resources.

Impact of Retinopathy and Systemic Vascular Comorbidities on All-Cause Mortality.

Purpose: To assess the impact of retinopathy and systemic vascular comorbidities on the all-cause mortality in a representative U.S. sample. Methods: A total of 5703 participants (≥40 years old) from the 2005-2008 National Health and Nutrition Examination Survey. The Early Treatment Diabetic Retinopathy Study grading scale was used to evaluate the retinopathy status. Systemic vascular comorbidities included diabetes mellitus (DM), high blood pressure (HBP), chronic kidney disease (CKD) and cardiovascular disease (CVD). Time to death was calculated as the time from baseline to either the date of death or censoring (December 31st, 2015), whichever came first. Risks of mortality were estimated using Cox proportional hazards models after adjusting for confounders and vascular comorbidities. Results: After a median follow-up of 8.33 years (IQR: 7.50-9.67 years), there were 949 (11.8%) deaths from all causes. After adjusting for confounders, the presence of retinopathy predicted higher all-cause mortality (hazard ratio (HR), 1.41; 95% confidence interval (CI), 1.08-1.83). The all-cause mortality among participants with both retinopathy and systemic vascular comorbidities including DM (HR, 1.72; 95% CI, 1.21-2.43), HBP (HR, 1.47; 95% CI, 1.03-2.10), CKD (HR, 1.73; 95% CI, 1.26-2.39) and CVD (HR, 1.92; 95% CI, 1.21-3.04) was significantly higher than that among those without either condition. When stratified by diabetic or hypertension status, the co-occurrence of retinopathy and CKD or CVD further increased the all-cause mortality compared to those without either condition. Conclusions: The co-occurrence of retinopathy and systemic vascular conditions predicted a further increase in the risk of mortality. More extensive vascular risk factor assessment and management are needed to detect the burden of vascular pathologies and improve long-term survival in individuals with retinopathy.