Safety of SGLT2i with regard to bone and mineral metabolism in patients with CKD.

PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a relatively new class of oral glucose-lowering agents that reduce adverse cardiovascular and kidney outcomes among individuals with chronic kidney disease (CKD). Emerging evidence suggests that SGLT2i may also affect bone and mineral metabolism. This review analyzes recent evidence on the safety of SGLT2i with respect to bone and mineral metabolism in people with CKD, and discusses potential underlying mechanisms and clinical implications. RECENT FINDINGS: Recent studies have documented the beneficial effects of SGLT2i on cardiovascular and renal outcomes among individuals with CKD. SGLT2i may alter renal tubular phosphate reabsorption and are associated with increased serum concentrations of phosphate, fibroblast growth factor-23 (FGF-23), parathyroid hormone (PTH), decreased 1,25-hydroxyvitamin D levels, as well as increased bone turnover. Clinical trials have not demonstrated an increased risk of bone fracture associated with SGLT2i use among patients with CKD with or without diabetes mellitus. SUMMARY: Although SGLT2i are associated with abnormalities of bone and mineral metabolism, they have not been linked to a higher risk of fracture among patients with CKD. More research is needed on the association between SGLT2i and fracture risk in this population.

Diabetic kidney disease and risk of incident stroke among adults with type 2 diabetes.

BACKGROUND: Data on the relations between kidney function abnormalities and stroke in type 2 diabetes are limited. We evaluated the associations of kidney function abnormalities and chronic kidney disease (CKD) stages with incident stroke in a large sample of adults with type 2 diabetes. METHODS: Participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study without history of stroke at baseline were included. Urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were assessed at baseline. CKD categories were defined according to the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) for stroke in relation to measures of kidney function and CKD categories. RESULTS: A total of 9170 participants (mean age 62.8 [SD: 6.6] years, 38.2% women, 62.9% white) were included. Over a median follow-up of 4.9 years (interquartile range: 4.0-5.7), 156 participants developed a stroke (incidence rate 3.6/1000 person-years [95% CI 3.0-4.2]). After adjusting for relevant confounders, higher UACR and lower eGFR were each associated with increased risk of stroke. Compared to UACR < 30 mg/g, moderate albuminuria and severe albuminuria were associated with increasing hazards for stroke (HR 1.61 [95% CI 1.12-2.32] and 2.29 [95% CI 1.39-3.80], respectively). Compared to eGFR of ≥ 60 mL/min/1.73 m2, decreased eGFR (eGFR < 60 mL/min/1.73 m2) was associated with higher risk of stroke (HR 1.50, 95% CI 0.98-2.29). Compared to no CKD, worsening CKD stage was associated with an increasing risk of stroke (HRs of 1.76 [95% CI 1.10-2.83] for CKD G1, 1.77 [95% CI 1.13-2.75] for CKD G2, and 2.03 [95% CI 1.27-3.24] for CKD G3). CONCLUSIONS: In a large sample of adults with type 2 diabetes, increasing albuminuria and worsening stages of early CKD were independently associated with higher risk of incident stroke. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT00000620 .

Association of plasma endothelin-1 with blood pressure progression among Blacks: The Jackson Heart Study.

BACKGROUND: Despite pathophysiological links between endothelin (ET)-1 and hypertension in Black adults, there is no population-based data appraising the association of plasma ET-1 with longitudinal blood pressure (BP) changes in Blacks. METHODS: We analyzed data from 1197 Jackson Heart Study participants without hypertension (mean age 47.8 years [SD: 12.0]; 64.2% women), with plasma ET-1 available at the baseline examination (2000-2004). Poisson regression with robust variance was used to generate risk ratios (RRs) and 95% confidence intervals (CIs) of BP progression (an increase by ≥1 BP category based on the 2017 American College of Cardiology/American Heart Association classification) and incident hypertension (BP ≥ 130/80 mm Hg or use of antihypertensive medication) at follow-up (2005-2008 or 2009-2013). RESULTS: Over a median follow-up of 7 years (range: 4-11), 71.2% (n = 854) progressed to a higher BP stage and 64.6% (n = 773) developed hypertension. After adjusting for possible confounders, each unit increment in baseline log (ET-1) was associated with higher risks of BP progression (RR 1.15 [95% CI 1.03-1.29], P = .016) and incident hypertension (RR 1.15 [95% CI 1.01-1.31], P = .032). Compared to those in the lowest ET-1 quartile, participants in the highest quartile had significantly higher risks of BP progression (RR 1.20 [95% CI 1.05-1.37], P = .007) and incident hypertension (RR 1.16 [95% CI 1.00-1.36], P = .052). CONCLUSIONS: In a large, community-based sample of African Americans, higher plasma ET-1 concentrations were associated with higher risks of BP progression and incident hypertension.

Association of SGLT2 inhibitors with cardiovascular, kidney, and safety outcomes among patients with diabetic kidney disease: a meta-analysis.

BACKGROUND: We conducted a systematic review and meta-analysis of the cardiovascular, kidney, and safety outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients with diabetic kidney disease (DKD). METHODS: We searched electronic databases for major randomized placebo-controlled clinical trials published up to September 30, 2021 and reporting on cardiovascular and kidney outcomes of SGLT2i in patients with DKD. DKD was defined as chronic kidney disease in individuals with type 2 diabetes. Random-effects meta-analysis models were used to estimate pooled hazard ratios (HR) and 95% confidence intervals (CI) for clinical outcomes including major adverse cardiovascular events (MACE: myocardial infarction [MI], stroke, and cardiovascular death), kidney composite outcomes (a combination of worsening kidney function, end-stage kidney disease, or death from renal or cardiovascular causes), hospitalizations for heart failure (HHF), deaths and safety events (mycotic infections, diabetic ketoacidosis [DKA], volume depletion, amputations, fractures, urinary tract infections [UTI], acute kidney injury [AKI], and hyperkalemia). RESULTS: A total of 26,106 participants with DKD from 8 large-scale trials were included (median age: 65.2 years, 29.7-41.8% women, 53.2-93.2% White, median follow-up: 2.5 years). SGLT2i were associated with reduced risks of MACE (HR 0.83, 95% CI 0.75-0.93), kidney composite outcomes (HR 0.66, 95% CI 0.58-0.75), HHF (HR 0.62, 95% CI 0.55-0.71), cardiovascular death (HR 0.84, 95% CI 0.74-0.96), MI (HR 0.78, 95% CI 0.67-0.92), stroke (HR 0.76, 95% CI 0.59-0.97), and all-cause death (HR 0.86, 95% CI 0.77-0.96), with no significant heterogeneity detected. Similar results were observed among participants with reduced estimated glomerular filtration rate (eGFR: < 60 mL/min/1.73m2). The relative risks (95% CI) for adverse events were 3.89 (1.42-10.62) and 2.50 (1.32-4.72) for mycotic infections in men and women respectively, 3.54 (0.82-15.39) for DKA, and 1.29 (1.13-1.48) for volume depletion. CONCLUSIONS: Among adults with DKD, SGLT2i were associated with reduced risks of MACE, kidney outcomes, HHF, and death. With a few exceptions of more clear safety signals, we found overall limited data on the associations between SGLT2i and safety outcomes. More research is needed on the safety profile of SGLT2i in this population.

Variability of adiposity indices and incident heart failure among adults with type 2 diabetes.

BACKGROUND: It remains unclear how the variability of adiposity indices relates to incident HF. This study evaluated the associations of the variability in several adiposity indices with incident heart failure (HF) in individuals with type 2 diabetes (T2DM). METHODS: We included 4073 participants from the Look AHEAD (Action for Health in Diabetes) study. We assessed variability of body mass index (BMI), waist circumference (WC), and body weight across four annual visits using three variability metrics, the variability independent of the mean (VIM), coefficient of variation (CV), and intraindividual standard deviation (SD). Multivariable Cox regression models were used to generate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for incident HF. RESULTS: Over a median of 6.7 years, 120 participants developed incident HF. After adjusting for relevant confounders including baseline adiposity levels, the aHR for the highest (Q4) versus lowest quartile (Q1) of VIM of BMI was 3.61 (95% CI 1.91-6.80). The corresponding aHRs for CV and SD of BMI were 2.48 (95% CI 1.36-4.53) and 2.88 (1.52-5.46), respectively. Regarding WC variability, the equivalent aHRs were 1.90 (95% CI 1.11-3.26), 1.79 (95% CI 1.07-3.01), and 1.73 (1.01-2.95) for Q4 versus Q1 of VIM, CV and SD of WC, respectively. CONCLUSIONS: In a large sample of adults with T2DM, a greater variability of adiposity indices was associated with higher risks of incident HF, independently of traditional risk factors and baseline adiposity levels. Registration-URL: https://clinicaltrials.gov/ct2/show/NCT00000620 .

Association of heart rate variability with progression of retinopathy among adults with type 2 diabetes.

AIM: We evaluated the associations of heart rate variability (HRV) with incident vision-threatening retinopathy and retinopathy progression among adults with type 2 diabetes. METHODS: Participants recruited to the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study with HRV measures at baseline were analysed. HRV measures included standard deviation of all normal-to-normal intervals (SDNN) and root mean square of successive differences between normal-to-normal intervals (rMSSD). Low SDNN was defined as SDNN <8.2 ms; low rMSSD as rMSSD <8.0 ms. We used multivariable adjusted Cox proportional hazards and modified Poisson regression models to generate risk estimates for incident vision-threatening retinopathy and retinopathy progression, respectively. RESULTS: A total of 5810 participants without incident vision-threatening retinopathy at baseline (mean age 62 years, 40.5% women, 63.5% White) were included. Over a median of 4.7 years, 280 incident vision-threatening retinopathy cases requiring treatment occurred. Low HRV (vs. normal HRV) was associated with higher risk of incident vision-threatening retinopathy (adjusted hazard ratio 1.32 [95%CI 1.03-1.71] and 1.14 [95%CI 1.01-1.28] for low SDNN and rMSSD, respectively). In the subset of 2184 participants with complete eye examinations at baseline and 4 years, 191 experienced retinopathy progression, and low HRV (vs. normal HRV) was associated with a higher risk of retinopathy progression (adjusted relative risks 1.36 [95%CI 1.01-1.83] and 1.36 [95%CI 1.01-1.84] for low SDNN and rMSSD, respectively). CONCLUSIONS: Cardiac autonomic neuropathy, as assessed by low HRV, was independently associated with increased risks of incident vision-threatening retinopathy and overall retinopathy progression in a large cohort of adults with type 2 diabetes.

Plasma adipokines and glycaemic progression among African Americans: Findings from the Jackson Heart Study.

AIM: To evaluate the association between plasma biomarkers including leptin, adiponectin, adiponectin-to-leptin ratio and high-sensitivity C-reactive protein (hsCRP) with risk of glycaemic progression and incident dysglycaemia (pre-diabetes or diabetes) in a community-based sample of African American (AAs). METHODS: We analysed data from 3223 participants without type 2 diabetes at baseline (2000-2004) who attended ≥1 follow-up visit. Poisson regression was used to generate risk ratios (RRs) for glycaemic progression and incident dysglycaemia. RESULTS: Over a median of 7 years, 46.4% developed glycaemic progression (n=1495). After adjusting for demographic and lifestyle variables, the RRs (95% CI) for glycaemic progression comparing highest (Q4) to lowest (Q1) quartiles were 1.30 (1.10-1.54), 0.74 (0.65-0.84), 0.70 (0.62-0.80) and 1.22 (1.07-1.38) for leptin, adiponectin, adiponectin-leptin ratio and hsCRP, respectively. Upon additional adjustment for BMI, the corresponding RRs (95% CIs) were 1.15 (0.94-1.42), 0.76 (0.67-0.86), 0.72 (0.62-0.84) and 1.14 (0.99-1.31) respectively. Among participants with normal glycaemia, the RRs (95% CIs) for incident pre-diabetes in Q4 vs Q1 were 1.37 (1.13-1.67), 0.73 (0.63-0.85), 0.70 (0.59-0.82) and 1.28 (1.10-1.48) for leptin, adiponectin, adiponectin-leptin ratio and hsCRP, respectively; equivalent RRs for incident diabetes were 5.15 (2.63-10.10), 0.36 (0.20-0.68), 0.21 (0.12-0.38) and 3.04 (1.70-5.44), respectively. CONCLUSIONS: In this large community-based cohort of AAs, our results suggest that high plasma leptin and hsCRP, as well as low adiponectin and adiponectin-to-leptin ratio, are associated with higher risks of glycaemic progression. The findings point to the potential utility of these biomarkers in predicting and preventing glycaemic progression in this high-risk population.

The Prognostic Value of Histopathologic Lesions in Native Kidney Biopsy Specimens: Results from the Boston Kidney Biopsy Cohort Study.

Background Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data.Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression (≥40% eGFR decline or RRT).Results Mean baseline eGFR was 57.5±36.0 ml/min per 1.73 m2 During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27).Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.

Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD.

BACKGROUND: Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown. STUDY DESIGN: Prospective observational cohort study. SETTINGS & PARTICIPANTS: 3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March 2013. PREDICTOR: Baseline uric acid concentrations. OUTCOMES: Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality. RESULTS: During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs) ≥ 45mL/min/1.73m2 (adjusted HR per 1-standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs<30mL/min/1.73m2. There was a nominally higher HR in participants with eGFRs of 30 to 44mL/min/1.73m2 (adjusted HR, 1.13; 95% CI, 0.99-1.29), but this did not reach statistical significance. The relationship between uric acid concentration and all-cause mortality was J-shaped (P=0.007). LIMITATIONS: Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time. CONCLUSIONS: Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD.

Incidence and Risk Factors for Prediabetes and Diabetes Mellitus Among HIV-infected Adults on Antiretroviral Therapy: A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize evidence on the rates and drivers of progression from normoglycemia to prediabetes and/or diabetes mellitus (hereafter "diabetes") in antiretroviral treatment (ART)-exposed HIV-infected people. METHODS: We searched EMBASE, PubMed, Web of Science, and Global Index Medicus to identify articles published from 1 January 2000 to 30 April 2017. A random-effects model produced a summary estimate of the incidence across studies and heterogeneity was assessed using Cochrane's Q statistic. RESULTS: We included 44 studies, whose methodologic quality was high with only 10 (30%) medium-quality studies and none of low quality. There was substantial heterogeneity between studies in estimates of the incidence of diabetes and prediabetes. The pooled incidence rate of overt diabetes and prediabetes were 13.7 per 1,000 person-years of follow-up (95% CI = 13, 20; I = 98.1%) among 396,496 person-years and 125 per 1,000 person-years (95% CI = 0, 123; I = 99.4) among 1,532 person-years, respectively. The major risk factors for diabetes and prediabetes were aging, family history of diabetes, Black or Hispanic origin, overweight/obesity, central obesity, lipodystrophy/lipoatrophy, dyslipidemia, metabolic syndrome, increased baseline fasting glycemia, and certain ART regimens. CONCLUSIONS: These data highlight the important and fast-increasing burden of diabetes and prediabetes among the ART-exposed HIV-infected population. More research is needed to better capture the interplay between prediabetes/diabetes and ART in HIV-infected patients, considering the increasing number of ART-exposed patients subsequent to the World Health Organization's recommendation of initiating ART at HIV infection diagnosis regardless of CD4 count and age.

Burden of chronic kidney disease on the African continent: a systematic review and meta-analysis.

BACKGROUND: Accurate contemporary data on the burden of Chronic Kidney Disease (CKD) on the African continent are lacking. We determined the prevalence of CKD in adult populations living in Africa, and variations by stage, gender, estimated Glomerular Filtration Rate (eGFR) equation, and residence. METHODS: For this systematic review, we searched multiple electronic databases for original studies on CKD prevalence reported from January 1, 2000 to December 31, 2016. Two reviewers independently undertook quality assessment and data extraction. We stabilized the variance of study-specific estimates with the Freeman-Turkey single arcsine transformation and pooled the data using a random effects meta-analysis models. RESULTS: A total of 98 studies involving 98,432 individuals were included in the final meta-analysis. The overall prevalence was 15.8% (95% CI 12.1-19.9) for CKD stages 1-5 and 4.6% (3.3-6.1) for CKD stages 3-5 in the general population. Equivalent figures were greater at 32.3% (23.4-41.8) and 13.3% (10.7-16.0) in high-risk populations (people with hypertension, diabetes, HIV). CKD prevalence was higher in studies based on the Cockcroft-Gault formula than MDRD or CKD-EPI equations; and in studies from sub-Saharan Africa compared with those from North Africa (17.7, 95% CI 13.7-22.1 vs 6.1, 95% CI 3.6-9.3, p < 0.001). There was substantial heterogeneity across studies (all I2 > 90%) and no evidence of publication bias in main analyses. CONCLUSION: CKD is highly prevalent across Africa, inviting efforts into prevention, early detection and control of CKD in adults living on the African continent which is particularly important in a resource limited environment. TRIAL REGISTRATION: Prospero Registration ID: CRD42017054445 .

Non-tunneled versus tunneled dialysis catheters for acute kidney injury requiring renal replacement therapy: a prospective cohort study.

BACKGROUND: Acute kidney injury requiring renal replacement therapy (AKI-RRT) is associated with high morbidity, mortality and resource utilization. The type of vascular access placed for AKI-RRT is an important decision, for which there is a lack of evidence-based guidelines. METHODS: We conducted a prospective cohort study over a 16-month period with 154 patients initiated on AKI-RRT via either a non-tunneled dialysis catheter (NTDC) or a tunneled dialysis catheter (TDC) at an academic hospital. We compared differences in renal replacement delivery and mechanical and infectious outcomes between NTDCs and TDCs. RESULTS: Patients who received TDCs had significantly better RRT delivery, both with continuous venovenous hemofiltration (CVVH) and intermittent hemodialysis (IHD), compared to patients who received NTDCs; these findings were confirmed after multivariable adjustment for AKI-specific disease severity score, history of chronic kidney disease, renal consult team, and AKI cause. In CVVH and IHD, the median venous and arterial blood flow pressures were significantly higher with TDCs compared to NTDCs (p < 0.001). Additionally for CVVH, the median number of interruptions per catheter was higher with NTDCs compared to TDCs (Rate Ratio (RR) 2.7; p < 0.001), and for IHD, a higher median blood flow was seen with TDCs (p < 0.001). There were a significantly higher number of mechanical complications with NTDCs (RR 13.6 p = 0.001). No significant difference was observed between TDCs and NTDCs for positive blood cultures per catheter. CONCLUSIONS: Compared to NTDCs, TDCs for patients with AKI-RRT had improved RRT delivery and fewer mechanical complications. Initial TDC placement for AKI-RRT should be considered when not clinically contraindicated given the potential for improved RRT delivery and outcomes.

Association Between Microvascular Disease and Cardiorespiratory Fitness Among Adults With Type 2 Diabetes.

OBJECTIVE: Little is known about the extent to which microvascular disease is associated with cardiorespiratory fitness (CRF) among individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 4,766 participants with type 2 diabetes underwent maximal exercise testing in the Look AHEAD (Action for Health in Diabetes) study at baseline. Low CRF was defined based on the Aerobics Center Longitudinal Study reference standards. Microvascular disease was defined as having one or more of diabetes-related kidney disease (DKD), retinopathy, and neuropathy. The burden of microvascular disease was defined as the number of microvascular beds affected. RESULTS: Of the 4,766 participants (mean age 58.9 ± 6.7 years, 58.5% women, 66.1% White individuals), 1,761 (37%) had microvascular disease. Participants with microvascular complications in three vascular territories had a lower CFR than those without any microvascular disease (mean adjusted metabolic equivalent of task [MET] 6.58 vs. 7.26, P = 0.001). Participants with any microvascular disease had higher odds of low CRF than those without microvascular disease (adjusted odds ratio [OR] 1.45, 95% CI 1.24-1.71). An increasing burden of microvascular disease was associated with higher odds of low CRF (for microvascular disease in three vascular territories, adjusted OR 2.82, 95% CI 1.36-5.85). Adjusted ORs for low CRF were 1.24 (95% CI 0.99-1.55), 1.34 (95% CI 1.02-1.76), and 1.44 (95% CI 1.20-1.73) for neuropathy, retinopathy, and DKD associations, respectively. CONCLUSIONS: In a large cohort of adults with type 2 diabetes, the presence of microvascular disease and its burden were independently associated with lower CRF.

Cardiac Autonomic Dysfunction and Risk of Silent Myocardial Infarction Among Adults With Type 2 Diabetes.

Background There is a paucity of large-scale epidemiological studies on the link between cardiac autonomic neuropathy (CAN) and the risk of silent myocardial infarction (SMI) in type 2 diabetes. We evaluated the association between CAN and the risk of SMI in a large sample of adults with type 2 diabetes. Methods and Results Participants with type 2 diabetes from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study without atherosclerotic cardiovascular disease at baseline were included. CAN was ascertained using heart rate variability indices calculated from 10-s resting electrocardiograms. The heart rate variability indices included standard deviation of all normal-to-normal R-R intervals and root mean square of successive differences between normal-to-normal R-R intervals. CAN was defined as both the standard deviation of all normal-to-normal R-R intervals and root mean square of successive differences between normal-to-normal R-R intervals less than the fifth percentile of the general population. We used Cox proportional hazards regression to generate hazard ratios (HRs) for incident SMI in relation to CAN measures. Among 4842 participants (mean age, 62.5 years; 46.6% women; 60.2% White), there were 73 incident SMI cases over a median follow-up of 4.9 years (incidence rate 3.1 out of 1000 person-years [95% CI, 2.5-3.9]). After adjusting for confounders, low heart rate variability was associated with a higher risk of SMI (HR, 1.67 [95% CI, 1.02-2.72] and HR, 1.56 [95% CI, 0.94-2.58] for low standard deviation of all normal-to-normal R-R intervals and root mean square of successive differences between normal-to-normal R-R intervals, respectively). Participants with CAN had a 1.9-fold greater risk of SMI (HR, 1.91 [95% CI, 1.14-3.20]). Conclusions In a large cohort of adults with type 2 diabetes, CAN was significantly associated with an increased risk of incident SMI.

Blood Pressure Variability and Risk of Atrial Fibrillation in Adults With Type 2 Diabetes.

BACKGROUND: There is a paucity of epidemiological data on the association between long-term variability of blood pressure (BP) and incident atrial fibrillation (AF). OBJECTIVES: The purpose of this study was to evaluate the association of BP variability with incident AF in a large sample of adults with type 2 diabetes. METHODS: We included participants who had ≥5 BP measurements in the first 24 months of action to control cardiovascular risk in diabetes. The visit-to-visit variability of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was estimated using the coefficient of variation, SD, and variability independent of the mean. Incident AF was recorded using follow-up electrocardiograms. Modified Poisson regression was used to generate risk ratios (RRs) and 95% CI for AF. RESULTS: A total of 8,399 participants were included (average age 62.6 ± 6.5 years, 38.8% women, 63.2% White). Over a median follow-up of 5 years, 155 developed AF. Compared to the lowest quartile, the highest quartile of BP variability was associated with an increased risk of AF (RR: 1.85 [95% CI: 1.13-3.03] and 1.63 [95% CI: 1.01-2.65] for coefficient of variation of SBP and DBP, respectively). Participants in the highest quartile of both SBP and DBP had a 2-fold higher risk of AF compared to those in the lowest 3 quartiles of both SBP and DBP (RR: 1.94; 95% CI: 1.29-2.93). CONCLUSIONS: In a large cohort of adults with type 2 diabetes, higher variability in SBP and DBP was independently associated with an increased risk of AF.

Cardiac autonomic dysfunction and risk of incident stroke among adults with type 2 diabetes.

Introduction: There is a dearth of data on the association between cardiac autonomic neuropathy (CAN) with incident stroke among individuals with diabetes mellitus. We evaluated this association in a large sample of adults with type 2 diabetes. Patients and methods: Participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study without atherosclerotic cardiovascular disease at baseline were included. CAN was assessed at baseline by heart rate variability (HRV) indices and QT index (QTI) calculated from 10-s resting electrocardiograms. HRV was assessed using standard deviation of all normal-to-normal R-Rs intervals (SDNN) and root mean square of successive differences between normal-to-normal R-R intervals (rMSSD). CAN was defined based on several composite measures of SDNN, QTI, resting heart rate and peripheral neuropathy. We used Cox proportional hazards regression to generate hazard ratios (HR) and 95% confidence intervals (CI) for incident stroke in relation to CAN. Results: A total of 3493 participants (mean age 62.2 years, 44.5% women, 62.9% White) were included. Over a median follow-up of 5.0 years, 50 stroke cases occurred (incidence rate 3.0/1000 person-years [95% CI 2.2-3.9]). After adjusting for confounders, low HRV was associated with a higher risk of stroke (HR of 2.20 [95% CI 1.23-3.93] and 1.88 [95% CI 1.04-3.41] for low SDNN and rMSSD, respectively). Participants with CAN (defined as lowest quartile of SDNN and highest quartiles of QTI and heart rate) had a 5.7-fold greater risk of stroke (HR 5.70, 95% CI 2.49-13.08). Discussion and conclusion: CAN was independently associated with an increased risk of incident stroke in a large cohort of adults with type 2 diabetes.

Association between physical activity and clinical outcomes in high-risk hypertension: Post-hoc analysis of SPRINT.

Objective: Engaging in physical activity (PA) is recommended to reduce the risk of morbidity and mortality in patients with hypertension. However, the association between PA and clinical outcomes in individuals with high-risk hypertension is understudied. We examined the relationship between PA and clinical outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT). SPRINT investigated the benefit of intensive (vs. standard) blood pressure treatment in patients with high-risk hypertension. Methods: Baseline data on PA was self-reported. Vigorous-intensity PA (VPA) was categorized into 2 groups based on frequency of "Rarely or Never" and 1 or more sessions/month. Moderate-intensity PA (MPA) was also categorized into 2 groups based on average duration/day of <15 min and 15 or more minutes. Using multivariable Cox regression, we estimated the associations between PA the primary outcome which was a composite of cardiovascular events, and all-cause mortality. Results: A total of 8,320 (age 67.8 ± 9.3, 34.9% women) of SPRINT participants with data on PA were included. During a median follow-up of 3.8 years, 619 primary outcome, and 419 all-cause mortality events occurred. Compared to not engaging in VPA, the risk of the primary outcome, myocardial infarction, and all-cause mortality (HR 95% CIs) associated with VPA of ≥1sessions/month was 0.79(0.65-0.94; p=0.009), 0.70(0.52-0.93; p=0.014) and 0.75(0.60-0.94; p=0.011), respectively. Similarly, the risk of the primary outcome and all-cause mortality (HR 95% CI) associated with engaging in MPA for ≥15 min/day, relative to <15 min/day was 0.76(0.63-0.93; p=0.008) and 0.80(0.62-1.02; p=0.066), respectively. Conclusion: Among individuals with hypertension from the SPRINT study, VPA and MPA at a threshold of ≥1sessions/month and MPA of ≥15 min/day respectively, were both associated with a lower risk for cardiovascular events, and VPA was also associated with a reduced risk for all-cause mortality. Further studies are required to identify the optimal volume and intensity of PA in high-risk hypertension.

Association between weight variability, weight change and clinical outcomes in hypertension.

Objective: The effect of body weight variability (BWV) and body weight change (BWC) in high-risk individuals with hypertension, but without diabetes mellitus (DM) remains unclear. We examined the effect of BWV and BWC on the primary outcome [the composite of myocardial infarction (MI), other acute coronary syndromes, stroke, acute decompensated heart failure (HF), or cardiovascular (CV) death] and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). Methods: In this post-hoc analysis, we used multivariate Cox regression models to examine the risk associated with BWV and BWC for the primary outcome in SPRINT. BWV was defined as the intra-individual average successive variability (ASV). BWC was defined as baseline weight minus final weight. Results: A total of 8714 SPRINT participants (mean age 67.8 ± 9.4 years, 35.1 % women, 58.9 % Whites) with available data on body weight were included. The median follow-up was about 3.9 years (IQR, 3.3-4.4). In multivariable-adjusted Cox models, each 1 unit standard deviation (SD) of BWV was significantly associated with a higher risk for the primary outcome, all-cause mortality, HF, MI, and stroke [HR(95 % CI)]: 1.13 (1.07-1.19; p < 0.0001), 1.22 (1.14-1.30; p < 0.0001), 1.16 (1.07-1.26; p < 0.001), 1.10 (1.00-1.20; p = 0.047), and 1.15 (1.05-1.27; p = 0.005), respectively. Similarly, each 1 unit SD of BWC was significantly associated with a higher risk of the primary outcome, all-cause mortality, MI, and HF: 1.11(1.02-1.21; p = 0.017), 1.44 (1.26-1.65; p < 0.0001), 1.16 (1.01-1.32; p = 0.041) and 1.19 (1.02-1.40; p = 0.031) respectively. However, there was no significant association with CV death (for both BWV and BWC) or stroke (BWC). Conclusion: In high-risk hypertension, BWV and BWC were both associated with higher risk of the primary outcome and all-cause mortality. These results further stress the clinical importance of sustained weight loss and minimizing fluctuations in weight in hypertension.

Burden of Microvascular Disease and Risk of Atrial Fibrillation in Adults with Type 2 Diabetes.

BACKGROUND: Epidemiological data on the associations of microvascular disease with atrial fibrillation are scarce. We evaluated the associations of diabetes-related microvascular disease in multiple vascular beds and its burden with incident atrial fibrillation among adults with type 2 diabetes. METHODS: A total of 7603 participants with type 2 diabetes and without atrial fibrillation were assessed for diabetic kidney disease, retinopathy, or neuropathy at baseline in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Incident atrial fibrillation events were adjudicated using follow-up electrocardiograms. Modified Poisson regression was used to generate risk ratios (RRs) and 95% confidence intervals (CIs) for atrial fibrillation. RESULTS: Of the 7603 participants (mean age 62.5 years, 38.0% women, 63.4% white), 63.3% (n = 4816) had microvascular disease-defined as the presence of ≥1 of: diabetic kidney disease, retinopathy, or neuropathy at baseline. Over a median of 7 years, there were 137 atrial fibrillation events (1.8%). Participants with microvascular disease had a 1.9-fold higher risk of incident atrial fibrillation compared with those without microvascular disease (RR 1.88; 95% CI, 1.20-2.95). Compared with no microvascular disease, the RRs for atrial fibrillation were 1.62 (95% CI, 1.01-2.61) and 2.47 (95% CI, 1.46-4.16) for those with 1 and ≥2 microvascular territories affected, respectively. The RRs for atrial fibrillation by type of microvascular disease were 1.57 (95% CI, 1.09-2.26), 0.95 (95% CI, 0.53-1.70), and 1.67 (95% CI, 1.15-2.44) for neuropathy, retinopathy, and diabetic kidney disease, respectively. CONCLUSIONS: In a large cohort of adults with type 2 diabetes, the presence of microvascular disease and its burden were independently associated with higher risk of incident atrial fibrillation.