Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

BACKGROUND: Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. METHODS: Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. FINDINGS: Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. INTERPRETATION: Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.

Late Holocene summer temperatures in the central Andes reconstructed from the sediments of high-elevatin Laguna Chepical, Chile (32° S)

High-resolution reconstructions of climate variability that cover the past millennia are necessary to improve the understanding of natural and anthropogenic climate change across the globe. Although numerous records are available for the mid- and high-latitudes of the Northern Hemisphere, global assessments are still compromised by the scarcity of data from the Southern Hemisphere. This is particularly the case for the tropical and subtropical areas. In addition, high elevation sites in the South American Andes may provide insight into the vertical structure of climate change in the mid-troposphere. This study presents a 3000 yr-long austral summer (November to February) temperature reconstruction derived from the 210Pb- and 14C-dated organic sediments of Laguna Chepical (32°16' S, 70°30' W, 3050 m a.s.l.), a high-elevation glacial lake in the subtropical Andes of central Chile. Scanning reflectance spectroscopy in the visible light range provided the spectral index R570/R630, which reflects the clay mineral content in lake sediments. For the calibration period (AD 1901–2006), the R570/R630 data were regressed against monthly meteorological reanalysis data, showing that this proxy was strongly and significantly correlated with mean summer (NDJF) temperatures (R3 yr = −0.63, padj = 0.01). This calibration model was used to make a quantitative temperature reconstruction back to 1000 BC. The reconstruction (with a model error RMSEPboot of 0.33 °C) shows that the warmest decades of the past 3000 yr occurred during the calibration period. The 19th century (end of the Little Ice Age (LIA)) was cool. The prominent warmth reconstructed for the 18th century, which was also observed in other records from this area, seems systematic for subtropical and southern South America but remains difficult to explain. Except for this warm period, the LIA was generally characterized by cool summers. Back to AD 1400, the results from this study compare remarkably well to low altitude records from the Chilean Central Valley and southern South America. However, the reconstruction from Laguna Chepical does not show a warm Medieval Climate Anomaly during the 12–13th century, which is consistent with records from tropical South America. The Chepical record also indicates substantial cooling prior to 800 BC. This coincides with well-known regional as well as global glacier advances which have been attributed to a grand solar minimum. This study thus provides insight into the climatic drivers and temperature patterns in a region for which currently very few data are available. It also shows that since ca. AD 1400, long-term temperature patterns were generally similar at low and high altitudes in central Chile.

Cold-season temperatures in the European Alps during the past millennium: variability, seasonality and recent trends

This study presents a proxy-based, quantitative reconstruction of cold-season (mean October to May, TOct–May) air temperatures covering nearly the entire last millennium (AD 1060–2003, some hiatuses). The reconstruction was based on subfossil chrysophyte stomatocyst remains in the varved sediments of high-Alpine Lake Silvaplana, eastern Swiss Alps (46°27’N, 9°48′W, 1791 m a.s.l.). Previous studies have demonstrated the reliability of this proxy by comparison to meteorological data. Cold-season air temperatures could therefore be reconstructed quantitatively, at a high resolution (5-yr) and with high chronological accuracy. Spatial correlation analysis suggests that the reconstruction reflects cold season climate variability over the high- Alpine region and substantial parts of central and western Europe. Cold-season temperatures were characterized by a relatively stable first part of the millennium until AD 1440 (2σ of 5-yr mean values = 0.7 °C) and highly variable TOct–May after that (AD 1440–1900, 2σ of 5-yr mean values = 1.3 °C). Recent decades (AD, 1991-present) were unusually warm in the context of the last millennium (exceeding the 2σ-range of the mean decadal TOct–May) but this warmth was not unprecedented. The coolest decades occurred from AD 1510–1520 and AD 1880–1890. The timing of extremely warm and cold decades is generally in good agreement with documentary data representing Switzerland and central European lowlands. The transition from relatively stable to highly variable TOct–May coincided with large changes in atmospheric circulation patterns in the North Atlantic region. Comparison of reconstructed cold season temperatures to the North Atlantic Oscillation index (NAO) during the past 1000 years showed that the relatively stable and warm conditions at the study site until AD 1440 coincided with a persistent positive mode of the NAO. We propose that the transition to large TOct–May variability around AD 1440 was linked to the subsequent absence of this persistent zonal flow pattern, which would allow other climatic drivers to gain importance in the study area. From AD 1440–1900, the similarity of reconstructed TOct–May to reconstructed air pressure in the Siberian High suggests a relatively strong influence of continental anticyclonic systems on Alpine cold season climate parameters during periods when westerly airflow was subdued. A more continental type of atmospheric circulation thus seems to be characteristic for the Little Ice Age in Europe. Comparison of Toct–May to summer temperature reconstructions from the same study site shows that, as expected, summer and cold season temperature trends and variability differed completely throughout nearly the entire last 1000 years. Since AD 1980, however, summer and cold season temperatures show a simultaneous, strong increase, which is unprecedented in the context of the last millennium. We suggest that the most likely explanation for this recent trend is anthropogenic greenhouse gas (GHG) forcing.

A chrysophyte stomatocyst-based reconstruction of cold-season air temperature from Alpine Lake Silvaplana (AD 1500–2003); methods and concepts for quantitative inferences

Relatively little is known about past cold-season temperature variability in high-Alpine regions because of a lack of natural cold-season temperature proxies as well as under-representation of high-altitude sites in meteorological, early-instrumental and documentary data sources. Recent studies have shown that chrysophyte stomatocysts, or simply cysts (sub-fossil algal remains of Chrysophyceae and Synurophyceae), are among the very few natural proxies that can be used to reconstruct cold-season temperatures. This study presents a quantitative, high-resolution (5-year), cold-season (Oct–May) temperature reconstruction based on sub-fossil chrysophyte stomatocysts in the annually laminated (varved) sediments of high-Alpine Lake Silvaplana, SE Switzerland (1,789 m a.s.l.), since AD 1500. We first explore the method used to translate an ecologically meaningful variable based on a biological proxy into a simple climate variable. A transfer function was applied to reconstruct the ‘date of spring mixing’ from cyst assemblages. Next, statistical regression models were tested to convert the reconstructed ‘dates of spring mixing’ into cold-season surface air temperatures with associated errors. The strengths and weaknesses of this approach are thoroughly tested. One much-debated, basic assumption for reconstructions (‘stationarity’), which states that only the environmental variable of interest has influenced cyst assemblages and the influence of confounding variables is negligible over time, is addressed in detail. Our inferences show that past cold-season air-temperature fluctuations were substantial and larger than those of other temperature reconstructions for Europe and the Alpine region. Interestingly, in this study, recent cold-season temperatures only just exceed those of previous, multi-decadal warm phases since AD 1500. These findings highlight the importance of local studies to assess natural climate variability at high altitudes.

Ecosystem impacts of feral rabbits on World Heritage sub-Antarctic Macquarie Island: A palaeoecological perspective

The introduction and establishment of non-indigenous species through human activities often poses a major threat to natural biodiversity. In many parts of the world management efforts are therefore focused on their eradication. The environment of World Heritage sub-Antarctic Macquarie Island has been severely damaged by non-indigenous species including rabbits, rats and mice, introduced from the late AD 1800s. An extensive eradication programme is now underway which aims to remove all rabbits and rodents. To provide a long-term context for assessing the Island's pre-invasion state, invasion impacts, and to provide a baseline for monitoring its recovery, we undertook a palaeoecological study using proxies in a lake sediment core. Sedimentological and diatom analyses revealed an unproductive catchment and lake environment persisted for ca. 7100 years prior to the introduction of the invasive species. After ca. AD 1898, unprecedented and statistically significant environmental changes occurred. Lake sediment accumulation rates increased >100 times due to enhanced catchment inputs and within-lake production. Total carbon and total nitrogen contents of the sediments increased by a factor of four. The diatom flora became dominated by two previously rare species. The results strongly suggest a causal link between the anthropogenic introduction of rabbits and the changes identified in the lake sediments. This study provides an example of how palaeoecology may be used to determine baseline conditions prior to the introduction of non-indigenous species, quantify the timing and extent of changes, and help monitor the recovery of the ecosystem and natural biodiversity following successful non-indigenous species eradication programmes.

Urbanization, socio-economic changes and population growth in Brazil: dietary shifts and environmental implications.

Population growth, economic globalization, improving living standards and urbanization are causing important changes in the global food system and modifying the dietary habits in many parts of the world (Molden, 2007; Godfray et al., 2010). The nutritional transition (linked to the development of countries and the increasing wealth of its population) implies a shift away from traditional staple food such as roots and tuber vegetables and a rise in consumption of meat and milk products, refined and processed foods, as well as sugars, oils and fats (Ambler-Edwards et al., 2009). The contemporary food system puts significant pressure on natural resources, especially on land and water, because the growing food demand pushes the agricultural frontier beyond, causing large impacts on ecosystems (Ambler-Edwards et al. 2009: 11-18). Also, the trend towards richer diets in animal proteins and processed food adds further pressure on the environment, since it requires larger amount of water and land to be produced (Allan, 2011; Mekonnen and Hoekstra, 2012).

A water footprint assessment of a pair of jeans: the influence of agricultural policies on the sustainability of consumer products.

This study reports the results of a water footprint (WF) assessment of five types of textiles commonly used for the production of jeans, including two different fibres (cotton and Lyocell fibre) and five corresponding production methods for spinning, dyeing and weaving. The results show that the fibre production is the stage with the highest water consumption, being cotton production particularly relevant. Therefore, the study pays particular attention to the water footprint of cotton production and analyses the effects of external factors influencing the water footprint of a product, in this case, the incentives provided by the EU Common Agricultural Policy (CAP), and the relevance of agricultural practices to the water footprint of a product is emphasised. An extensification of the crop production led to higher WF per unit, but a lower overall pressure on the basins water resources. This study performs a sustainability assessment of the estimated cotton WFs with the water scarcity index, as proposed by Hoekstra et al. (2011), and shows their variations in different years as a result of different water consumption by crops in the rest of the river basin. In our case, we applied the assessment to the Guadalquivir, Guadalete and Barbate river basins, three semi-arid rivers in South Spain. Because they are found to be relevant, the available water stored in dams and the outflow are also incorporated as reference points for the sustainability assessment. The study concludes that, in the case of Spanish cotton production, the situation of the basin and the policy impact are more relevant for the status of the basin s water resources than the actual WF of cotton production. Therefore, strategies aimed at reducing the impact of the water footprint of a product need to analyse both the WF along the value chain and within the local context.