Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Functional diversity mediates macroecological variation in plant–hummingbird interaction networks

© 2018 John Wiley & Sons Ltd Aim: Species interaction networks are known to vary in structure over large spatial scales. We investigated the hypothesis that environmental factors affect interaction network structure by influencing the functional diversity of ecological communities. Notably, we expect more functionally diverse communities to form interaction networks with a higher degree of niche partitioning. Location: Americas. Time period: Current. Major taxa studied: Hummingbirds and their nectar plants. Methods: We used a large dataset comprising 74 quantitative plant–hummingbird interaction networks distributed across the Americas, along with morphological trait data for 158 hummingbird species. First, we used a model selection approach to evaluate associations between the environment (climate, topography and insularity), species richness and hummingbird functional diversity as predictors of network structure (niche partitioning, i.e., complementary specialization and modularity). Second, we used structural equation models (SEMs) to ask whether environmental predictors and species richness affect network structure directly and/or indirectly through their influence on hummingbird functional diversity. For a subset of 28 networks, we additionally evaluated whether plant functional diversity was associated with hummingbird functional diversity and network structure. Results: Precipitation, insularity and plant richness, together with hummingbird functional diversity (specifically, functional dispersion), were consistently strong predictors of niche partitioning in plant–hummingbird networks. Moreover, SEMs showed that environmental predictors and plant richness affected network structure both directly and indirectly through their effects on hummingbird functional diversity. Plant functional diversity, however, was unrelated to hummingbird functional diversity and network structure. Main conclusions: We reveal the importance of hummingbird functional diversity for niche partitioning in plant–hummingbird interaction networks. The lack of support for similar effects for plant functional diversity potentially indicates that consumer functional diversity might be more important for structuring interaction networks than resource functional diversity. Changes in pollinator functional diversity are therefore likely to alter the structure of interaction networks and associated ecosystem functions

The influence of biogeographical and evolutionary histories on morphological trait‐matching and resource specialization in mutualistic hummingbird–plant networks

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordData availability statement: Data deposited in the Dryad Digital Repository: https://doi.org/10.5061/dryad.rr4xgxd7n, (Dalsgaard et al., 2021).1. Functional traits can determine pairwise species interactions, such as those between plants and pollinators. However, the effects of biogeography and evolutionary history on trait-matching and trait-mediated resource specialization remain poorly understood. 2. We compiled a database of 93 mutualistic hummingbird-plant networks (including 181 hummingbird and 1,256 plant species), complemented by morphological measures of hummingbird bill and floral corolla length. We divided the hummingbirds into their principal clades and used knowledge on hummingbird biogeography to divide the networks into four biogeographical regions: Lowland South America, Andes, North & Central America, and the Caribbean islands. We then tested: (i) whether hummingbird clades and biogeographical regions differ in hummingbird bill length, corolla length of visited flowers and resource specialization, and (ii) whether hummingbirds’ bill length correlates with the corolla length of their food plants and with their level of resource specialization. 3. Hummingbird clades dominated by long-billed species generally visited longer flowers and were the most exclusive in their resource use. Bill and corolla length and the degree of resource specialization were similar across mainland regions, but the Caribbean islands had shorter flowers and hummingbirds with more generalized interaction niches. Bill and corolla length correlated in all regions and most clades, i.e. trait-matching was a recurrent phenomenon in hummingbird-plant associations. In contrast, bill length did not generally mediate resource specialization, as bill length was only weakly correlated with resource specialization within one hummingbird clade (Brilliants) and in the regions of Lowland South America and the Andes in which plants and hummingbirds have a long co-evolutionary history. Supplementary analyses including bill curvature confirmed that bill morphology (length and curvature) does not in general predict resource specialization. 4. These results demonstrate how biogeographical and evolutionary histories can modulate the effects of functional traits on species interactions, and that traits better predict functional groups of interaction partners (i.e. trait-matching) than resource specialization. These findings reveal that functional traits have great potential, but also key limitations, as a tool for developing more mechanistic approaches in community ecologyIndependent Research Fund DenmarkDanish National Research FoundationCAPESCNPqESDEPED-UATxFAPESBConsejo Nacional para Investigaciones Científicas y Tecnológicas (CONICIT)Hesse’s Ministry of Higher Education, Research, and the ArtsNational Council of Science and Technology (CONACYT)Instituto de EcologíaCOLCIENCIASFundación ProAvesAmerican Bird ConservancyRoyal Commission for the Exhibition of 1851US ArmyCERL-ERDCBritish Ecological SocietyBiodiversity TrustAnglo Peruvian SocietyEuropean Union Horizon 202

The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics

Background: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. Methods: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin ­versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of â\u88¼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate â\u89¥30 to 300 to â\u89¤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. Conclusion: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. Trial Registration: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791