Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding: Novo Nordisk

Devastating Decline of Forest Elephants in Central Africa.

African forest elephants– taxonomically and functionally unique–are being poached at accelerating rates, but we lack range-wide information on the repercussions. Analysis of the largest survey dataset ever assembled for forest elephants (80 foot-surveys; covering 13,000 km; 91,600 person-days of fieldwork) revealed that population size declined by ca. 62% between 2002–2011, and the taxon lost 30% of its geographical range. The population is now less than 10% of its potential size, occupying less than 25% of its potential range. High human population density, hunting intensity, absence of law enforcement, poor governance, and proximity to expanding infrastructure are the strongest predictors of decline. To save the remaining African forest elephants, illegal poaching for ivory and encroachment into core elephant habitat must be stopped. In addition, the international demand for ivory, which fuels illegal trade, must be dramatically reduced

Encounter rate of hunter sign per kilometre.

<p>Results are shown for the 80 survey sites in Central Africa included in this study. Grey shading represents forest cover.</p

Percentage breakdown of the total number of forest elephants by country.

<p>Results are shown for 3 time periods: pre-1970s and 1989 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059469#pone.0059469-Michelmore1" target="_blank">[41]</a> and 2011 (this study).</p

Estimated conditional dependence of elephant dung density for top-ranked multi-variable models including hunter sign.

<p>Results are shown for the top-ranked model with variables: (A) hunter sign*, (B) survey year*, (C) proximity to roads∧, (D) human population density***, (E) corruption*** (higher values = less corrupt) and presence/absence of guards***. Also shown is (F) the Human Influence Index (HII) for the model with proximity to road and human population density variables replaced by the HII, i.e. one of the top-ranking models with variables: hunter sign**, survey year*, HII*, corruption***, and presence/absence of guards***. P-value significance codes are: ‘***’<0.001, ‘**’<0.01, ‘*’<0.05, and ‘∧’<0.1. Plot components are: Estimates on the scale of the linear predictor (solid lines) with the y-axis scale for each variable selected to optimally display the results, confidence intervals (dashed lines), and explanatory variable values of observations with a focus on the core 95% of values for hunter sign, proximity to road and human population density (rug plot - short vertical bars along each x-axis showing the x value for each site).</p

Boxplots of indices of elephant abundance and hunting intensity.

<p>Summaries shown are the natural logarithm of: (A) elephant dung encounter rate per 100 km grouped by the presence/absence of wildlife guards, (B) elephant dung encounter rate per 100 km grouped by the level of hunting intensity (group cutpoints are 0.6 and 1.75 hunter sign/km), and (C) hunter-sign frequency per 100 km grouped by the presence/absence of wildlife guards. Box-widths are proportional to the number of observations in each group.</p

Estimated change in elephant dung density (/km²) distribution during 2002–2011 across the Central African forests.

<p>Results are shown as a percentage of the total area of potential elephant habitat overall (A & B) and by country (C & D) for the predictive model with variables: (A & C) survey year, Human Influence Index, corruption and the presence/absence of guards, and (B & D) survey year, proximity to road, human population density, corruption and the presence/absence of guards. The dung density (per km²) intervals are unequal and correspond to the following elephant population categories: extremely low density (0–100), very low (100–250), low (250–500), medium (500–1,000), high (1,000–3,000) and very high (3,000–7,500). With the loss of very high elephant populations in 2011, there is a significant shift into the lower density intervals over the nine years.</p

Elephant dung density and range reduction across the Central African forests.

<p>Predictions are shown for (A) 2002 and (B) 2011 for the model with variables: survey year∧, Human Influence Index***, corruption*** and the presence/absence of guards***, and (C) 2002 and (D) 2011 for the model with variables: survey year∧, proximity to road∧, human population density***, corruption*** and the presence/absence of guards*** (P-values are: ‘***’ <0.001 and ‘∧’ <0.1). Increasingly darker shades of green correspond to higher densities, grey represents extremely low elephant density range (the first interval: 0–100 elephant dung piles/km²) and white is non-habitat (80 survey sites outlined in red). Cutpoints are: 0; 100; 250; 500; 1,000; 1,500; 3,000; 5,000; and 7,500 dung piles/km². Countries 1–5 are: Cameroon; Central African Republic; Republic of Congo; DRC; Gabon.</p

Encounter rate of elephant dung per kilometre.

<p>Results are shown for the 80 survey sites in Central Africa included in this study. Grey shading represents forest cover.</p