Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Changes in Philornis infestation behavior threaten Darwin's finch survival

The conservation behavior framework is useful to identify key linkages between behavior and conservation practice. We apply this framework to a novel host-parasite system on the Galapagos Islands and ask if there have been changes in parasite oviposition behavior and host mortality patterns across the first decade (2004-2013) of its known association. The Dipteran parasite Philornis downsi was first discovered in Darwin's finch nests in 1997 and is the biggest threat to the survival of Galapagos land birds. Host mortality has increased over the past decade. In Dipterans, pupation and pupae size are determined by access to host resources. Here, we test the hypothesis that P. downsi flies are laying eggs in finch nests earlier in the nestling phase to maximize larval feeding time and therefore chance of pupation success before host death. The results show fewer 1st instar larvae later in the host nesting cycle in support of earlier egg laying behavior by female flies. Between 2004 and 2013, parasite intensity increased from similar to 28 to similar to 48 parasites per nest, host mortality increased from similar to 50% to similar to 90%, and host age at death decreased from similar to 11 to similar to 5 days. The earlier age at host death was correlated with fewer pupae (from similar to 50% to similar to 20%) and smaller pupae size (similar to 10% decrease). Changes in parasite behavior reveal new fitness costs to both the parasite and Darwin's finches. These findings underscore the need for urgent conservation action to save Darwin's finches from extinction due to a novel, lethal and introduced parasit

Data from: Females drive asymmetrical introgression from rare to common species in Darwin's tree finches

The consequences of hybridization for biodiversity depend on the specific ecological and evolutionary context in which it occurs. Understanding patterns of gene flow among hybridizing species is crucial for determining the evolutionary trajectories of species assemblages. The recently discovered hybridization between two species of Darwin's tree finches (Camarhynchus parvulus and C. pauper) on Floreana Island, Galápagos, presents an exciting opportunity to investigate the mechanisms causing hybridization and its potential evolutionary consequences under conditions of recent habitat disturbance and the introduction of invasive pathogens. In this study, we combine morphological and genetic analysis with pairing observations to explore the extent, direction and drivers of hybridization and to test if hybridization patterns are a result of asymmetrical pairing preference driven by females of the rarer species (C. pauper). We found asymmetrical introgression from the critically endangered, larger-bodied C. pauper to the common, smaller-bodied C. parvulus, which was associated with a lack of selection against heterospecific males by C. pauper females. Examination of pairing data showed that C. parvulus females paired assortatively while C. pauper females showed no such pattern. This study shows how sex-specific drivers can determine the direction of gene flow in hybridizing species. Furthermore, our results suggest the existence of a hybrid swarm comprised of C. parvulus and hybrid birds. We discuss the influence of interspecific abundance differences and susceptibility to the invasive parasite Philornis downsi on the observed hybridisation and recommend that the conservation of this iconic species group should be managed jointly rather than species-specific

Changes in Philornis infestation behavior threaten Darwin's finch survival

The conservation behavior framework is useful to identify key linkages between behavior and conservation practice. We apply this framework to a novel host-parasite system on the Galapagos Islands and ask if there have been changes in parasite oviposition behavior and host mortality patterns across the first decade (2004-2013) of its known association. The Dipteran parasite Philornis downsi was first discovered in Darwin's finch nests in 1997 and is the biggest threat to the survival of Galapagos land birds. Host mortality has increased over the past decade. In Dipterans, pupation and pupae size are determined by access to host resources. Here, we test the hypothesis that P. downsi flies are laying eggs in finch nests earlier in the nestling phase to maximize larval feeding time and therefore chance of pupation success before host death. The results show fewer 1st instar larvae later in the host nesting cycle in support of earlier egg laying behavior by female flies. Between 2004 and 2013, parasite intensity increased from ~28 to ~48 parasites per nest, host mortality increased from ~50% to ~90%, and host age at death decreased from ~11 to ~5 days. The earlier age at host death was correlated with fewer pupae (from ~50% to ~20%) and smaller pupae size (~10% decrease). Changes in parasite behavior reveal new fitness costs to both the parasite and Darwin's finches. These findings underscore the need for urgent conservation action to save Darwin's finches from extinction due to a novel, lethal and introduced parasite.9 page(s

Parasite infestation and predation in Darwin's small ground finch: contrasting two elevational habitats between islands

Contrasting ecological conditions may affect the distribution, abundance and impact of parasites and predators throughout the ranges of hosts and prey. Such patterns are evident on the archipelagos of Hawaii and the Galapagos, which vary in their distribution and abundance of avian parasites within and across islands. Previous research has documented higher intensity of parasitic fly larvae (Philornis downsi) in nests of Darwin's finches on elevated islands of the Galapagos. Here we examine P. downsi intensity and predation in 71 nests of Darwin's small ground finch (Geospiza fuliginosa) on Floreana Island. We found significant differences in parasite intensity, nest predation and clutch size between the lowland (0-100 m) and highland (300-400 m) habitats. Lowland finch nests had few P. downsi parasites (mean of 8 per nest), high nest predation (44% of nests) and large clutch size (3.4). Highland finch nests showed the opposite pattern, with many P. downsi parasites (40 per nest), low nest predation (17%) and small clutch size (2.5). This study suggests that the impacts of an introduced parasite are limited by its niche requirements and resource availability within and across islands. Our findings also imply that the vulnerability of bird populations to introduced parasites and predators is linked with variation in life history strategies across habitats.8 page(s

Species collapse via hybridization in Darwin's tree finches

Species hybridization can lead to fitness costs, species collapse, and novel evolutionary trajectories in changing environments. Hybridization is predicted to be more common when environmental conditions change rapidly. Here, we test patterns of hybridization in three sympatric tree finch species (small tree finch Camarhynchus parvulus, medium tree finch Camarhynchus pauper, and large tree finch: Camarhynchus psittacula) that are currently recognized on Floreana Island, Galápagos Archipelago. Genetic analysis of microsatellite data from contemporary samples showed two genetic populations and one hybrid cluster in both 2005 and 2010; hybrid individuals were derived from genetic population 1 (small morph) and genetic population 2 (large morph). Females of the large and rare species were more likely to pair with males of the small common species. Finch populations differed in morphology in 1852-1906 compared with 2005/2010. An unsupervised clustering method showed (a) support for three morphological clusters in the historical tree finch sample (1852-1906), which is consistent with current species recognition; (b) support for two or three morphological clusters in 2005 with some (19%) hybridization; and (c) support for just two morphological clusters in 2010 with frequent (41%) hybridization. We discuss these findings in relation to species demarcations of Camarhynchus tree finches on Floreana Island.17 page(s

Assortative Pairing and Genetic Population_Am Nat

Assortative pairing, genetic and morphological data for male and female tree finches sampled on Floreana Island, Galapagos, 2005 and 2010. Techniques for measuring morphological features are described in the associated manuscript. Genetic population refers to population assignment based on analyses of microsatellite loci (using the program STRUCTURE)

Data from: Species collapse via hybridization in Darwin's tree finches

Species hybridization can lead to fitness costs, species collapse, and novel evolutionary trajectories in changing environments. Hybridization is predicted to be more common when environmental conditions change rapidly. Here, we test patterns of hybridization in three sympatric tree finch species (small tree finch Camarhynchus parvulus, medium tree finch Camarhynchus pauper, and large tree finch: Camarhynchus psittacula) that are currently recognized on Floreana Island, Galápagos Archipelago. Genetic analysis of microsatellite data from contemporary samples showed two genetic populations and one hybrid cluster in both 2005 and 2010; hybrid individuals were derived from genetic population 1 (small morph) and genetic population 2 (large morph). Females of the large and rare species were more likely to pair with males of the small common species. Finch populations differed in morphology in 1852–1906 compared with 2005/2010. An unsupervised clustering method showed (a) support for three morphological clusters in the historical tree finch sample (1852–1906), which is consistent with current species recognition; (b) support for two or three morphological clusters in 2005 with some (19%) hybridization; and (c) support for just two morphological clusters in 2010 with frequent (41%) hybridization. We discuss these findings in relation to species demarcations of Camarhynchus tree finches on Floreana Island

Allele size data Floreana Tree Finches 2005 & 2010

Allele size data for tree finches on Floreana Island, Galapagos. "Year" refers to whether an individual was sampled in 2005 or 2010. "FTA" is a unique number that was given to the blood sample of each sampled individual (this number was written next to blood samples stored on FTA paper). "Ring number" refers to the identifier inscribed on an aluminum band around a bird's tarsus. "Pop" refers to the species category given to each individual in the field: small tree finch=1, medium tree finch=2, large tree finch=3. Remaining information refers to allele size (maximum height at peak of allele) at each of 10 microsatellite loci (Gf01, Gf03, Gf04, Gf05, Gf06, Gf07, Gf09, Gf11, Gf12, Gf13

Philornis Intensity and Genetic Population Floreana Tree Finches_Am Nat

Total Philornis downsi larvae intensity per nest for tree finches breeding on Floreana Island in 2005, 2010 and 2012. Genetic population refers to population assignment based on analyses of microsatellite loci (using the program STRUCTURE). Male colour and putative species assignment are also provided (STF=small tree finch, MTF=medium tree finch, LTF= large tree finch)