Cardiovascular Outcomes According to Urinary Albumin and Kidney Disease in Patients With Type 2 Diabetes at High Cardiovascular Risk: Observations From the SAVOR-TIMI 53 Trial.
ABSTRACT: Importance:An elevated level of urinary albumin to creatinine ratio (UACR) is a marker of renal dysfunction and predictor of kidney failure/death in patients with type 2 diabetes. The prognostic use of UACR in established cardiac biomarkers is not well described. Objective:To evaluate whether UACR offers incremental prognostic benefit beyond risk factors and established plasma cardiovascular biomarkers. Design, Setting, and Participants:The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 study was performed from May 2010 to May 2013 and evaluated the safety of saxagliptin vs placebo in patients with type 2 diabetes with overt cardiovascular disease or multiple risk factors. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years). Interventions:Patients were randomized to saxagliptin vs placebo plus standard care. Main Outcomes and Measures:Baseline UACR was measured in 15?760 patients (95.6% of the trial population) and categorized into thresholds. Results:Of 15?760 patients, 5205 were female (33.0%). The distribution of UARC categories were: 5805 patients (36.8%) less than 10 mg/g, 3891 patients (24.7%) at 10 to 30 mg/g, 4426 patients (28.1%) at 30 to 300 mg/g, and 1638 patients (10.4%) at more than 300 mg/g. When evaluated without cardiac biomarkers, there was a stepwise increase with each higher UACR category in the incidence of the primary composite end point (cardiovascular death, myocardial infarction, or ischemic stroke) (3.9%, 6.9%, 9.2%, and 14.3%); cardiovascular death (1.4%, 2.6%, 4.1%, and 6.9%); and hospitalization for heart failure (1.5%, 2.5%, 4.0%, and 8.3%) (adjusted P?
Project description:In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury.In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days).Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported.The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.
Project description:Several studies show that even a level of urine albumin/creatinine ratio (UACR) within the normal range (below 30?mg/g) increases the risk of cardiovascular diseases. We speculate that mildly increased UACR is related to left ventricular hypertrophy (LVH) in patients with type 2 diabetes mellitus (T2DM). In this retrospective study, 317 patients with diabetes with normal UACR, of whom 62 had LVH, were included. The associations between UACR and laboratory indicators, as well as LVH, were examined using multivariate linear regression and logistic regression, respectively. The diagnostic efficiency and the optimal cutoff point of UACR for LVH were evaluated using the area under the receiver operating characteristic curve (AUC) and Youden index. Our results showed that patients with LVH had significantly higher UACR than those without LVH (P < 0.001). The prevalence of LVH presented an upward trend with the elevation of UACR. UACR was independently and positively associated with hemoglobin A1c (P < 0.001). UACR can differentiate LVH (AUC?=?0.682, 95% CI (0.602-0.760), P < 0.001). The optimal cutoff point determined with the Youden index was UACR?=?10.2?mg/g. When categorized by this cutoff point, the odds ratio (OR) for LVH in patients in the higher UACR group (10.2-30?mg/g) was 3.104 (95% CI: 1.557-6.188, P=0.001) compared with patients in the lower UACR group (<10.2?mg/g). When UACR was analyzed as a continuous variable, every double of increased UACR, the OR for LVH was 1.511 (95% CI: 1.047-2.180, P=0.028). Overall, UACR below 30?mg/g is associated with LVH in patients with T2DM. The optimal cutoff value of UACR for identifying LVH in diabetes is 10?mg/g.
Project description:Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as ?-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.
Project description:BACKGROUND:If SGLT2 inhibitors protect the kidneys by reducing albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher albuminuria should benefit more. METHODS:We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline albuminuria. The trial included 2266 participants (22.3%) with moderately increased albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased albuminuria (UACR >300 mg/g) at baseline. RESULTS:Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria (P heterogeneity<0.001). After week 13, canagliflozin slowed the annual loss of kidney function across albuminuria subgroups, with greater absolute reductions in participants with severely increased albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m2 per year; P heterogeneity<0.001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased albuminuria (P heterogeneity=0.03), but no effect modification was observed when albuminuria was fitted as a continuous variable (P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across albuminuria levels including increased risks for amputation across albuminuria subgroups (P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased albuminuria (P heterogeneity=0.004). CONCLUSIONS:The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of albuminuria, but absolute benefits are greatest among those with severely increased albuminuria.
Project description:There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.
Project description:AIMS:Type 2 diabetes is associated with endothelial dysfunction leading to cardiovascular disease. CD34+ endothelial Progenitor Cells (EPCs) are responsible for endothelial repair and neo-angiogenesis and can be used as a cardiovascular disease risk biomarker. This study investigated whether the addition of saxagliptin, a DPP-IV inhibitor, to metformin, may reduce cardiovascular disease risk in addition to improving glycemic control in Type 2 diabetes patients. METHODS:In 12 week, double-blind, randomized placebo-controlled trial, 42 subjects already taking metformin 1-2 grams/day were randomized to placebo or saxagliptin 5 mg. Subjects aged 40-70 years with diabetes for < 10 years, with no known cardiovascular disease, BMI 25-39.9, HbA1C 6-9% were included. We evaluated EPCs number, function, surface markers and gene expression, in addition to arterial stiffness, blood biochemistries, resting energy expenditure, and body composition parameters. A mixed model regression to examine saxagliptin vs placebo, accounting for within-subject autocorrelation, was done with SAS (p < 0.05). RESULTS:Although there was no significant increase in CD34+ cell number, CD31+ cells percentage increased. Saxagliptin increased migration (in response to SDF1α) with a trend of higher colony formation count. MNCs cytometry showed higher percentage of CXCR4 double positivity for both CD34 and CD31 positive cells, indicating a functional improvement. Gene expression analysis showed an upregulation in CD34+ cells for antioxidant SOD1 (p < 0.05) and a downregulation in CD34- cells for IL-6 (p < 0.01). For arterial stiffness, both augmentation index and systolic blood pressure measures went down in saxagliptin subjects (p < 0.05). CONCLUSION:Saxagliptin, in combination with metformin, can help improve endothelial dysfunction in early diabetes before macrovascular complications appear. Trial registration Trial is registered under clinicaltrials.gov, NCT02024477.
Project description:The sodium glucose co-transporter-2 inhibitor dapagliflozin has been shown to decrease urinary albumin-to-creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non-response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24 weeks, the UACR-adjusted mean change from baseline was -71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined.
Project description:BACKGROUND: Low-grade albuminuria is associated with cardiovascular risk factors and mortality. Our aim was to investigate the association between low-grade albuminuria and carotid atherosclerotic lesions in community-based patients with type 2 diabetes. METHODS: A cross-sectional study was performed in 475 community-based patients with type 2 diabetes (190 males and 285 females) with normal urinary albumin-to-creatinine ratios (UACR) (< 3.5 mg/mmol) from Shanghai, China. The subjects were stratified into tertiles based on UACR levels (the lowest tertile was UACR???1.19 mg/mmol, and the highest tertile was UACR???2 mg/mmol). Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on ultrasonography. The urinary albumin excretion rate was determined as the mean of the values obtained from three separate early morning urine samples. RESULTS: Compared with the subjects with UACR in the lowest tertile, the subjects with UACR in the middle and highest tertiles had greater CIMT values (0.88?±?0.35 mm, 0.99?±?0.43 mm and 1.04?±?0.35 mm, respectively; all p?<?0.05) and a higher prevalence of carotid atherosclerotic plaques (25.3%, 39.0% and 46.2%, respectively; all p?<?0.05) after adjusting for sex and age. Fully adjusted multiple linear regression and logistic regression analyses revealed that UACR tertiles were significantly associated with elevated CIMT (p?=?0.007) and that, compared with the subjects in the first tertile of UACR, those in the second and third tertiles had 1.878- and 2.028-fold risk of carotid plaques, respectively. However, there was no statistical association between UACR tertile and the prevalence of carotid stenosis. CONCLUSIONS: Higher UACR within the normal range was independently associated with early but not late carotid atherosclerotic lesions in community-based patients with type 2 diabetes. Low-grade albuminuria contributes to the risk of carotid atherosclerosis and may be used as an early marker for the detection of atherosclerosis in patients with type 2 diabetes.
Project description:Several types of cardiovascular diseases (CVDs) impair the physical and mental status. The purpose of this study was to assess the predictive ability of several cardiovascular biomarkers for identifying the incidence of disability as future recipients of public long-term care (LTC) service.The subjects of this study were community-dwelling elderly individuals ? 65 years of age without a history of CVD (n = 5,755; mean age, 71 years). The endpoint of this study was official certification as a recipient of LTC. The cohort was divided into quartiles (Qs) based on the levels of three CVD biomarkers: the urinary albumin-creatinine ratio (UACR), plasma B-type natriuretic peptide concentration (BNP), and serum high-sensitivity C-reactive protein concentration (hsCRP). A time-dependent Cox proportional hazard model was used to determine the multi-adjusted relative hazard ratios (HRs) for incident LTC among the quartiles of each biomarker.During the follow-up (mean 5.6 years), 710 subjects were authorized as recipients of LTC. The HR was only significantly increased in the higher Qs of UACR (Q3, p < 0.01; Q4, p < 0.001). However, other biomarkers were not significantly associated with the endpoint. The risk predictive performance for the incidence of LTC as evaluated by an essential model (i.e. age- and sex-adjusted) was significantly improved by incorporating the UACR (net reclassification improvement = 0.084, p < 0.01; integrated discrimination improvement = 0.0018, p < 0.01).These results suggest that an increased UACR is useful for predicting physical and cognitive dysfunction in an elderly general population.
Project description:OBJECTIVE:In people with type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular risk and progression of diabetic kidney disease. Our aim was to determine whether sotagliflozin (SOTA), a dual SGLT1i and SGLT2i, had favorable effects on clinical biomarkers suggestive of kidney protection in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS:In this 52-week pooled analysis, 1,575 adults enrolled in the inTandem1 and inTandem2 trials were randomized to SOTA 200 mg, 400 mg, or placebo in addition to optimized insulin therapy. Changes in cardiorenal biomarkers were assessed. RESULTS:At 52 weeks, in response to SOTA 200 and 400 mg, the placebo-corrected least squares mean change from baseline in estimated glomerular filtration rate was -2.0 mL/min/1.73 m2 (P = 0.010) and -0.5 mL/min/1.73 m2 (P = 0.52), respectively. Systolic blood pressure difference was -2.9 and -3.6 mmHg (P < 0.0001 for both); diastolic blood pressure changed by -1.4 (P = 0.0033) and -1.6 mmHg (P = 0.0008). In participants with baseline urinary albumin-to-creatinine ratio (UACR) ?30 mg/g, UACR decreased by 23.7% (P = 0.054) and 18.3% (P = 0.18) for SOTA 200 and SOTA 400 mg, respectively, versus placebo. Increases in serum albumin and hematocrit and reductions in uric acid were observed throughout 52 weeks with both SOTA doses. CONCLUSIONS:SOTA was associated with short- and long-term renal hemodynamic changes, which were similar to those seen with SGLT2i in type 2 diabetes. Further investigation around cardiorenal effects of SOTA in people with type 1 diabetes is justified.