A cohort study of sodium-glucose cotransporter-2 inhibitors after acute kidney injury among Veterans with diabetic kidney disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for several adverse outcomes among patients with diabetic kidney disease. Yet, optimal timing for SGLT2i after acute kidney injury (AKI) is uncertain, as are the providers responsible for post-AKI SGLT2i initiation. Using a retrospective cohort of United States Veterans with diabetes mellitus type 2 and proteinuria, we examined encounters by provider specialty before SGLT2i initiation and subsequent all-cause mortality after hospitalization with AKI, defined by a 50% or more rise in serum creatinine. Covariates included recovery, defined by return to a 110% or less of baseline creatinine, and time since AKI hospitalization. Among 21,330 eligible Veterans, 7,798 died (37%) and 6,562 received a SGLT2i (31%) over median follow-up of 2.1 years. Post-AKI SGLT2i use was associated with lower mortality risk [adjusted hazard ratio 0.63 (95% confidence interval 0.58-0.68)]. Compared with neither SGLT2i use nor recovery, mortality risk was similar with recovery without SGLT2i use [0.97 (0.91-1.02)] but was lower without recovery prior to SGLT2i use [0.62 (0.55-0.71)] and with SGLT2i use after recovery [0.60 (0.54-0.67)]. Finally, the effect of SGLT2i was stable over time (P for time-interaction 0.19). Thus, we observed reduced mortality with SGLT2i use after AKI among Veterans with diabetic kidney disease whether started earlier or later or before or after observed recovery. Hence, patients with diabetic kidney disease who receive a SGLT2i earlier after AKI experience no significant harm impacting mortality and experience a lower mortality risk than those who do not.

Association between exercise frequency with renal and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk.

BACKGROUND: Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. METHODS: Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. RESULTS: Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097-0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05). CONCLUSIONS: Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov.uniqueidentifier :NCT00153101.

End-stage renal disease and metalworking fluid exposure.

OBJECTIVE: Despite increasing prevalence of end-stage renal disease (ESRD), little attention has been directed to how occupational exposures may contribute to risk. Our objective was to investigate the relationship between metalworking fluids (MWF) and ESRD in a cohort of 36 703 male autoworkers. METHODS: We accounted for competing risk of death, using the subdistribution hazard approach to estimate subhazard ratios (sHRs) and 95% CIs in models with cubic splines for cumulative exposure to MWF (straight, soluble or synthetic). RESULTS: Based on 501 ESRD cases and 13 434 deaths, we did not observe an association between MWF and ESRD overall. We observed modest associations between MWF and ESRD classification of glomerulonephritis and diabetic nephropathy. For glomerulonephritis, the 60th percentile of straight MWF was associated with an 18% increased subhazard (sHR=1.18, 95% CI: 0.99 to 1.41). For diabetic nephropathy, the subhazard increased 28% at the 60th percentile of soluble MWF (sHR=1.28, 95% CI: 1.00 to 1.64). Differences by race suggest that black males may have higher disease rates following MWF exposure. CONCLUSIONS: Exposure to straight and soluble MWF may be related to ESRD classification, though this relationship should be further examined.

Peripheral Neuropathy and All-Cause and Cardiovascular Mortality in U.S. Adults : A Prospective Cohort Study.

BACKGROUND: Growing evidence indicates that peripheral neuropathy (PN) is common even in the absence of diabetes. However, the clinical sequelae of PN have not been quantified in the general population. OBJECTIVE: To assess the associations of PN with all-cause and cardiovascular mortality in the general adult population of the United States. DESIGN: Prospective cohort study. SETTING: NHANES (National Health and Nutrition Examination Survey), 1999 to 2004. PARTICIPANTS: 7116 adults aged 40 years or older who had standardized monofilament testing for PN. MEASUREMENTS: Cox regression to evaluate the associations of PN with all-cause and cardiovascular mortality after adjustment for demographic and cardiovascular risk factors, overall and stratified by diabetes status. RESULTS: The overall prevalence of PN (±SE) was 13.5% ± 0.5% (27.0% ± 1.4% in adults with diabetes and 11.6% ± 0.5% in adults without diabetes). During a median follow-up of 13 years, 2128 participants died, including 488 of cardiovascular causes. Incidence rates (per 1000 person-years) of all-cause mortality were 57.6 (95% CI, 48.4 to 68.7) in adults with diabetes and PN, 34.3 (CI, 30.3 to 38.8) in adults with PN but no diabetes, 27.1 (CI, 23.4 to 31.5) in adults with diabetes but no PN, and 13.0 (CI, 12.1 to 14.0) in adults with no diabetes and no PN. In adjusted models, PN was significantly associated with all-cause mortality (hazard ratio [HR], 1.49 [CI, 1.15 to 1.94]) and cardiovascular mortality (HR, 1.66 [CI, 1.07 to 2.57]) in participants with diabetes. In those without diabetes, PN was significantly associated with all-cause mortality (HR, 1.31 [CI, 1.15 to 1.50]), but the association between PN and cardiovascular mortality was not statistically significant after adjustment (HR, 1.27 [CI, 0.98 to 1.66]). LIMITATION: Prevalent cardiovascular disease was self-reported, and PN was defined by monofilament testing only. CONCLUSION: Peripheral neuropathy was common and was independently associated with mortality in the U.S. population, even in the absence of diabetes. These findings suggest that decreased sensation in the foot may be an underrecognized risk factor for death in the general population. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute of the National Institutes of Health.

Insulin resistance, diabetic kidney disease, and all-cause mortality in individuals with type 2 diabetes: a prospective cohort study.

BACKGROUND: It is unclear whether insulin resistance (IR) contributes to excess mortality in patients with type 2 diabetes independent of diabetic kidney disease (DKD), which is strongly associated with IR and is a major risk factor for cardiovascular disease (CVD), the main cause of death in these individuals. We tested this hypothesis in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events Italian Multicentre Study. METHODS: This observational, prospective, cohort study enrolled 15,773 patients with type 2 diabetes attending 19 Italian Diabetes Clinics in 2006-2008. Insulin sensitivity was assessed as estimated glucose disposal rate (eGDR), which was validated against the euglycaemic-hyperinsulinemic clamp technique. Vital status on October 31, 2015, was retrieved for 15,656 patients (99.3%). Participants were stratified by eGDR tertiles from T1 (≥ 5.35 mg/kg/min) to T3 (≤ 4.14 mg/kg/min, highest IR). RESULTS: CVD risk profile was worse in T2 and T3 vs T1. eGDR tertiles were independently associated with micro- and macroalbuminuria and the albuminuric DKD phenotypes (albuminuria with preserved or reduced estimated glomerular filtration rate [eGFR]) as well as with eGFR categories or the nonalbuminuric DKD phenotype. Over a 7.4-year follow-up, unadjusted death rates and mortality risks increased progressively across eGDR tertiles, but remained significantly elevated after adjustment only in T3 vs T1 (age- and gender- adjusted death rate, 22.35 vs 16.74 per 1000 person-years, p < 0.0001, and hazard ratio [HR] adjusted for multiple confounders including DKD, 1.140 [95% confidence interval [CI], 1.049-1.238], p = 0.002). However, eGDR was independently associated with mortality in participants with no DKD (adjusted HR, 1.214 [95% CI, 1.072-1.375], p = 0.002) and in those with nonalbuminuric DKD (1.276 [1.034-1.575], p = 0.023), but not in those with the albuminuric DKD phenotypes. Moreover, the association was stronger in males and in younger individuals and was observed in those without but not with prior CVD, though interaction was significant only for age. CONCLUSIONS: The proxy of insulin sensitivity eGDR predicts all-cause mortality in type 2 diabetes, independent of confounders including DKD. However, the impact of IR in individuals with albuminuric DKD may be mediated by its relationship with albuminuria. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00715481, retrospectively registered 15 July 2008.

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.

The cumulative impact of social determinants of health factors on mortality in adults with diabetes and chronic kidney disease.

BACKGROUND: A growing body of evidence supports the potential role of social determinants of health on health outcomes. However, few studies have examined the cumulative effect of social determinants of health on health outcomes in adults with chronic kidney disease (CKD) with or without diabetes. This study examined the cumulative impact of social determinants of health on mortality in U.S. adults with CKD and diabetes. METHODS: We analyzed data from National Health and Nutrition Examination Surveys (2005-2014) for 1376 adults age 20 and older (representing 7,579,967 U.S. adults) with CKD and diabetes. The primary outcome was all-cause mortality. CKD was based on estimated glomerular filtration rate and albuminuria. Diabetes was based on self-report or Hemoglobin A1c of ≥6.5%. Social determinants of health measures included family income to poverty ratio level, depression based on PHQ-9 score and food insecurity based on Food Security Survey Module. A dichotomous social determinant measure (absence vs presence of ≥1 adverse social determinants) and a cumulative social determinant score ranging from 0 to 3 was constructed based on all three measures. Cox proportional models were used to estimate the association between social determinants of health factors and mortality while controlling for covariates. RESULTS: Cumulative and dichotomous social determinants of health score were significantly associated with mortality after adjusting for demographics, lifestyle variables, glycemic control and comorbidities (HR = 1.41, 95%CI 1.18-1.68 and HR = 1.41, 95%CI 1.08-1.84, respectively). When investigating social determinants of health variables separately, after adjusting for covariates, depression (HR = 1.52, 95%CI 1.10-1.83) was significantly and independently associated with mortality, however, poverty and food insecurity were not statistically significant. CONCLUSIONS: Specific social determinants of health factors such as depression increase mortality in adults with chronic kidney disease and diabetes. Our findings suggest that interventions are needed to address adverse determinants of health in this population.

Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy.

BACKGROUND: Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. METHODS: A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. RESULTS: At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. CONCLUSIONS: Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

Sodium-Glucose Cotransporter-2 Inhibitors and Protection Against stroke in Patients with type 2 Diabetes and Impaired Renal Function: A Systematic Review and Meta-Analysis.

BACKGROUND: Recent evidence indicates that treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) may favorably affect the risk of stroke in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease. OBJECTIVES: This meta-analysis considered data from cardiovascular outcome trials (CVOTs) regarding the effect of SGLT2i treatment on stroke risk in T2DM patients with an emphasis on patients with impaired renal function. SELECTION CRITERIA: Double-blind randomized trials (RCTs) representing CVOTs were included if they compared SGLT2i add-on therapy with placebo, and reported stroke among primary or secondary endpoints. RESULTS: Six eligible multicenter RCTs were included. The pooled analysis of 5 RCTs (n = 40,393) showed a neutral effect on the risk of total stroke from treatment with SGLT2i vs. placebo (hazard ratio, HR 0.90, 95% CI: 0.74-1.09, p = 0.29, I2 = 58%). Subgroup analysis (4 RCTs) involving patients with impaired renal function (n = 17,072) demonstrated a significant benefit in favor of SGLT2i (HR: 0.66, 95% CI: 0.54-0.82, p<0.0001, I2 = 8%). The pooled analysis of 2 RCTs (n = 14,543) showed a significant reduction in the risk of hemorrhagic stroke in T2DM patients (HR: 0.46, 95% CI: 0.25-0.83, p = 0.01; I2 = 0). No differences were noticed regarding the risk of ischemic stroke (HR: 0.97, 95% CI: 0.85-1.12, p = 0.69; I2 = 0), non-fatal stroke (HR: 0.98, 95% CI: 0.83-1.16, p = 0.79, I2 = 28%), and fatal stroke (HR: 0.77, 95% CI: 0.50-1.17, p = 0.22, I2 = 0). CONCLUSIONS: Available data suggest that SGLT2i reduce the risk of total stroke in patients with T2DM and impaired renal function. Based on the findings of two RCTs, these drugs may offer a protection against hemorrhagic stroke.

Liraglutide and Renal Outcomes in Type 2 Diabetes.

BACKGROUND: In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown. METHODS: We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. RESULTS: A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively). CONCLUSIONS: This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .).

Global trend of diabetes mortality attributed to vascular complications, 2000-2016.

BACKGROUND: The global epidemic of diabetes mellitus continues to grow and affects developed and developing countries alike. Intensive glycemic control is thought to modify the risks for vascular complications, hence the risks for diabetes-related death. We investigated the trend of diabetic vascular complication-related deaths between 2000 and 2016 in the global diabetes landscape. METHODS: We collected 17 years of death certificates data from 108 countries in the World Health Organization mortality database between 2000 and 2016, with coding for diabetic complications. Crude and age-standardized proportions and rates were calculated. Trend analysis was done with annual average percentage change (AAPC) of rates computed by joinpoint regression. RESULTS: From 2000 through 2016, 7,108,145 deaths of diabetes were reported in the 108 countries. Among them, 26.8% (1,904,787 cases) were attributed to vascular complications in damaged organs, including the kidneys (1,355,085 cases, 71.1%), peripheral circulatory (515,293 cases, 27.1%), nerves (28,697 cases, 1.5%) and eyes (5751 cases, 0.3%). Overall, the age-standardized proportion of vascular complication-related mortality was 267.8 [95% confidence interval (95% CI), 267.5-268.1] cases per 1000 deaths and the rate was 53.6 (95% CI 53.5-53.7) cases per 100,000 person-years. Throughout the 17-year period, the overall age-standardized proportions of deaths attributable to vascular complications had increased 37.9%, while the overall age-standardized mortality rates related to vascular complications had increased 30.8% (AAPC = 1.9% [1.4-2.4%, p < 0.05]). These increases were predominantly driven by a 159.8% increase in the rate (AAPC = 2.7% [1.2-4.3%, p < 0.05]) from renal complications. Trends in the rates and AAPC of deaths varied by type of diabetes and of complications, as well as by countries, regions and domestic income. CONCLUSION: Diabetic vascular complication-related deaths had increased substantially during 2000-2016, mainly driven by the increased mortality of renal complications.

Relationship between ABO blood groups and cardiovascular disease in type 1 diabetes according to diabetic nephropathy status.

BACKGROUND: ABO blood groups have previously been associated with cardiovascular disease (CVD) in the general population. This study aimed to investigate the potential relationship between ABO blood groups and CVD in individuals with type 1 diabetes according to diabetic nephropathy (DN) status. METHODS: Adults with type 1 diabetes (4531 individuals) from the FinnDiane Study were evaluated. DN was determined by two out of three measurements of urinary albumin excretion rate. Albuminuria was defined as an excretion rate above 20 µg/min. CVD events were identified by linking the data with the Finnish Care Register for Health Care and the Finnish Cause of Death Register. Follow-up ranged from the baseline visit until a CVD event, death or the end of 2017. The impact of ABO blood groups on CVD risk was estimated by multivariable Cox-regression analyses adjusted for traditional risk factors. RESULTS: At baseline, the median age was 38.5 (IQR 29.2-47.9) years, 47.5% were female and median duration of diabetes was 20.9 (11.4-30.7) years. There were 893 incident ischemic heart disease (IHD) events, 301 ischemic strokes (IS), and 415 peripheral artery disease (PAD) events during a median follow up of 16.5 (IQR 12.8-18.6) years. The A blood group showed the highest risk of IHD versus the O blood group, when microalbuminuria was present. Comparing the population with microalbuminuria with those with normoalbuminuria, only the A blood group elevated the risk of IHD. This increased risk was neither explained by the FUT2 secretor phenotype nor by the A-genotype distribution. The risk of IS or PAD was no different among the ABO blood groups regardless of diabetic nephropathy stage. CONCLUSION: The A blood group is a risk factor for IHD in individuals with type 1 diabetes and microalbuminuria.

Peripheral arterial endothelial dysfunction predicts future cardiovascular events in diabetic patients with albuminuria: a prospective cohort study.

BACKGROUND: Reactive hyperemia-peripheral arterial tonometry (RH-PAT) is a noninvasive and simple test for evaluating the endothelial function. There has been sparse evidence on the usefulness of the RH-PAT index (RHI) in predicting future cardiovascular diseases among diabetic patients. METHODS: Asymptomatic diabetic patients with albuminuria were selected; their medical history and laboratory findings were evaluated every 3 to 4 months, respectively. The primary outcome was a composite of three-point major adverse cardiovascular events (3-point MACE): death from cardiovascular causes, acute coronary events, or nonfatal stroke. On the contrary, secondary outcomes included a composite of 3-point MACE, hospitalization for heart failure, or chronic kidney disease (CKD) progression. RHI was measured using the Endo-PAT2000 at the baseline. RHI < 1.67 was considered to indicate peripheral endothelial dysfunction (PED). RESULTS: In total, 149 subjects were included (mean age, 61.8 ± 9.2 years; duration of diabetes was 12 years). During the follow-up period (median, 49.7 months), of the 149 subjects, primary outcomes were detected in 12 (1 [2.3%] and 11 [10.5%] of those without and with PED, respectively). The presence of PED in baseline measurements significantly increased both primary and secondary outcomes, following adjustment for age, sex, hypertension, glycated hemoglobin, low-density lipoprotein cholesterol, triglyceride, systolic blood pressure, baseline estimated glomerular filtration rate, overt proteinuria, duration of diabetes, premedical history of ischemic events, anti-platelet agents, and smoking history (hazard ratio [HR]: 10.95; 95% confidence interval CI 1.00-119.91 for the primary outcome; HR, 4.12; 95% CI 1.37-12.41 for secondary outcome). In addition, PED could predict secondary outcomes independent of the risk score according to the American College of Cardiology/American Heart Association (HR: 3.24; 95% CI 1.14-9.17). CONCLUSIONS: PED can independently predict future cardiovascular events among diabetic patients with albuminuria.

Prognostic importance of visit-to-visit blood pressure variability 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 an increased visit-to-visit blood pressure variability (BP-VVV) for the future development of micro- and macrovascular complications in type 2 diabetes has been scarcely investigated and is largely unsettled. We aimed to evaluate it in a prospective long-term follow-up study with 632 individuals with type 2 diabetes. METHODS: BP-VVV parameters (systolic and diastolic standard deviations [SD] and variation coefficients) were measured during the first 24-months. Multivariate Cox analysis, adjusted for risk factors and mean BP levels, examined the associations between BP-VVV and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration, peripheral neuropathy) and macrovascular complications (total cardiovascular events [CVEs], major adverse CVEs [MACE] and cardiovascular and all-cause mortality). Improvement in risk discrimination was assessed by the C-statistic and integrated discrimination improvement (IDI) index. RESULTS: Over a median follow-up of 11.3 years, 162 patients had a CVE (132 MACE), and 212 patients died (95 from cardiovascular diseases); 153 newly-developed or worsened diabetic retinopathy, 193 achieved the renal composite outcome (121 newly-developed microalbuminuria and 95 deteriorated renal function), and 171 newly-developed or worsened peripheral neuropathy. Systolic BP-VVV was an independent predictor of MACE (hazard ratio: 1.25, 95% CI 1.03-1.51 for a 1-SD increase in 24-month SD), but not of total CVEs, cardiovascular and all-cause mortality, and of any microvascular outcome. However, no BP-VVV parameter significantly improved cardiovascular risk discrimination (increase in C-statistic 0.001, relative IDI 0.9%). CONCLUSIONS: Systolic BP-VVV was an independent predictor of MACE, but it did not improve cardiovascular risk stratification. The goal of anti-hypertensive treatment in patients with type 2 diabetes shall remain in controlling mean BP levels, not on decreasing their visit-to-visit variability.

Outcomes of autogenous fistulas and prosthetic grafts for hemodialysis access in diabetic and nondiabetic patients.

BACKGROUND: This study evaluated the effect of diabetes on outcomes of autogenous fistulas and prosthetic grafts for hemodialysis access in a large population-based cohort of patients. METHODS: A retrospective cohort study was conducted of all patients who initiated hemodialysis in the United States Renal Database System (2007-2014). The χ2 test, Student t-test, Kaplan-Meier analysis, log-rank test, and multivariable logistic and Cox regression analyses were employed to evaluate maturation, interventions, patency, infection, and mortality. RESULTS: The study of 381,622 patients comprised 303,307 (79.5%) autogenous fistulas and 78,315 (20.5%) prosthetic grafts placed in 231,134 (60.6%) diabetic patients and 150,488 (39.4%) nondiabetic patients. There was decrease in maturation for diabetics compared to nondiabetics who received autogenous fistulas (adjusted hazard ratio [aHR], 0.86; 95% confidence interval [CI], 0.83-0.88; P < .001) and prosthetic grafts (aHR, 0.88; 95% CI, 0.83-0.93; P < .001). Comparing diabetics vs nondiabetics, primary patency at 5 years was 19.4% vs 23.5% (P < .001) for autogenous fistulas and 9.1% vs 11.2% (P < .001) for prosthetic grafts. Primary assisted patency at 5 years was 35.2% vs 38.7% (P < .001) for autogenous fistulas and 17.2% vs 19.2% (P = .015) for prosthetic grafts. Secondary patency at 5 years was 44.8% vs 48.6% (P < .001) for autogenous fistulas and 34.1% vs 36.8% (P = .002) for prosthetic grafts. There was 5% decrease in primary patency (aHR, 0.95; 95% CI, 0.94-0.96; P < .001) for diabetics compared to nondiabetics who received autogenous fistulas. There was no difference in primary assisted and secondary patency for autogenous fistulas as well as primary, primary assisted, and secondary patency for prosthetic grafts in comparing diabetic to nondiabetic patients. There was also no significant difference in severe prosthetic graft infection between the groups (aHR, 0.99; 95% CI, 0.92-1.08; P = .90). There was a 19% increase in patient mortality for diabetic relative to nondiabetic autogenous fistula recipients (aHR, 1.19; 95% CI, 1.17-1.20; P < .001) and 12% increase for prosthetic graft recipients (aHR, 1.12; 95% CI, 1.10-1.15; P < .001). CONCLUSIONS: In this population-based cohort of hemodialysis patients, diabetes mellitus was associated with a decrease in patient survival, access maturation, and primary fistula patency. In contrast, there was no association between diabetes and prosthetic graft patency and severe prosthetic graft infection warranting excision.

New anti-diabetic agents: major advances with unanswered questions.

No abstract present.

Effects of ACE Inhibitors and Angiotensin Receptor Blockers in Normotensive Patients with Diabetic Kidney Disease.

The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in reducing the progression of albuminuria and risk of cardiovascular events in hypertensive patients with diabetic kidney disease (DKD) is well-documented. However, the efficacy and safety of these agents in normotensive patients with DKD are still controversial. MEDLINE, Embase, and Cochrane Library were searched for relevant random controlled trials. The odd risk (OR) reductions were calculated with a random-effects model. Decrease in albuminuria, changes in eGFR, major cardiovascular events, and drug-related adverse events were analyzed. Thirteen RCTs including 1282 patients were retrieved. Compared with placebo or other active agent groups, ACEIs or ARBs significantly decreased albuminuria (MD -80.28 mg/d, 95% CI -104.79 mg/d to -55.77 mg/d), and the efficacy is independent of changes in blood pressure and systolic blood pressure at baseline. The result of subanalysis showed the declining of albuminuria was more significantly in normotensive DKD patients with 2DM (p=0.005). No significant differences were found with regard to the declining of evaluated glomerular filtration rate (eGFR) (MD -0.29 ml/min/1.73 m2, 95% CI -2.99 to 2.41 ml/min/1.73 m2). There were no significant differences in the side effect of the drugs such as hypotension and hyperkalemia. This meta-analysis demonstrated that ACEIs or ARBs can decrease albuminuria to varying degree in normotensive patients with DKD, and better response occurred in patients with 2DM.

Predictors of intra-hospital mortality in patients with diabetic foot ulcers in Nigeria: data from the MEDFUN study.

BACKGROUND: Diabetic foot ulcers (DFU) are associated with high morbidity and mortality globally. Mortality in patients hospitalized for DFU in Nigeria is unacceptably high. This study was undertaken to determine factors that predict mortality in patients hospitalized for DFU in Nigeria. METHODS: The current study was part of Multi-centre Evaluation of Diabetic Foot Ulcer in Nigeria (MEDFUN), an observational study conducted in six tertiary healthcare institutions across the 6 geopolitical zones of Nigeria. Consecutive type 1 or 2 diabetic patients hospitalized for DFU who consented to participate were recruited and subjected to relevant clinical, biochemical, and radiological assessments and multidisciplinary care until discharge or death. Data for type 1 diabetes mellitus (DM) patients were expunged from current mortality analysis due to their small number. RESULTS: Three hundred and twenty-three type 2 DM subjects with mean age and mean duration of DM of 57.2 ± 11.4 years and 8.7 ± 5.8 years respectively participated in this study. The median duration of ulcers was 39 days with a range of 28 to 54 days and the majority (79.9%) presented with advanced ulcers of at least Wagner grade 3. Mortality of 21.4% was recorded in the study, with the highest mortality observed among subjects with Wagner grade 5. Variables significantly associated with mortality with their respective p values were DM duration more than 120 months (p 0.005), ulcer duration > 1 month (p 0.020), ulcer severity of Wagner grade 3 and above (p 0.001), peripheral arterial disease (p 0.005), proteinuria (p < 0.001), positive blood cultures (p < 0.001), low HDL (p < 0.001), shock at presentation (p < 0.001), cardiac failure (p 0.027), and renal impairment (p < 0.001). On Multivariate regression analysis, presence of bacteraemia (OR 5.053; 95% CI 2.572-9.428) and renal impairment (OR 2.838; 95% CI 1.349-5.971) were significantly predictive of mortality independent of other variables. CONCLUSIONS: This study showed high intra-hospital mortality among patients with DFU, with the majority of deaths occurring among those with advanced ulcers, bacteraemia, cardiac failure, and renal impairment. Prompt attention to these factors might help improve survival from DFU in Nigeria.

Sodium-glucose co-transporter-2 inhibitors: peculiar "hybrid" diuretics that protect from target organ damage and cardiovascular events.

AIMS: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been proven to lead to relevant cardiovascular benefits, regardless of glycemic control function. SGLT2i have on the one hand led to reduction in cardiovascular events such as heart failure and on the other hand to renal protection. Blood pressure reduction and kidney function play a central role in these outcomes. This focused review describes the main mechanisms and clinical aspects of SGLT2i. DATA SYNTHESIS: These drugs act on the proximal renal tubule and behave as diuretics with a "hybrid" mechanism, as they can favour both natriuresis and enhanced diuresis due to an osmotic effect dependent on glycosuria, resulting in blood pressure decrease. The exclusive peculiarity of these "diuretics", which distinguishes them from loop and thiazide diuretics, lies also in the activation of the tubule-glomerular feedback. CONCLUSIONS: This mechanism, resulting in modulation of arterioles' tone and renin secretion, contributes to the favorable outcomes, suggesting a wider use of SGLT2i in internal medicine, nephrology and cardiology.