This article is for research and educational purposes only. It does not constitute medical advice. Always consult a registered healthcare provider before making any medication decisions.
For most of the 20th century, the treatment of obesity and the treatment of heart disease were managed as separate clinical problems. Cardiologists focused on lipids, blood pressure, and platelet aggregation. Endocrinologists managed blood sugar. Weight was a risk factor, not a target. That framing began to shift with the arrival of GLP-1 receptor agonists, and it was overturned decisively by the SELECT trial, published in the New England Journal of Medicine in November 2023.
The SELECT trial enrolled over 17,000 adults with established cardiovascular disease and obesity, but without diabetes. It asked a direct question: does semaglutide reduce the risk of serious cardiovascular events in people who are overweight or obese but not diabetic? The answer was yes: a 20% reduction in major adverse cardiovascular events (MACE) compared to placebo. That result reshaped how cardiologists, endocrinologists, and GPs worldwide think about GLP-1 therapy.
This article examines what SELECT found, why the cardiovascular benefit appears to go beyond weight reduction alone, how it fits into the broader evidence from earlier trials in diabetic populations, and what it means for Australian patients and prescribers navigating PBS access.
SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) was a phase 3b, randomised, double-blind, placebo-controlled, event-driven superiority trial conducted across 804 sites in 41 countries, including Australia. The study was published by Lincoff et al. in the New England Journal of Medicine (DOI: 10.1056/NEJMoa2307563).
Inclusion criteria were specific and clinically important:
This is a population that would not have qualified for PBS-subsidised semaglutide under diabetes indications, and at the time of the trial would not have been considered primary candidates for GLP-1 therapy at all. That is what makes SELECT methodologically distinctive: it isolated the cardiovascular signal from the glucose-lowering effect that had defined earlier GLP-1 outcomes trials.
The primary endpoint was a composite of MACE: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Participants received weekly subcutaneous semaglutide 2.4 mg (the Wegovy dose) or placebo, on top of standard-of-care management including statins, antihypertensives, and antiplatelet agents.
Over a mean follow-up of approximately 40 months, semaglutide reduced the primary MACE endpoint by 20% (HR 0.80, 95% CI 0.72–0.90; p<0.001). All three components of the composite trended in the same direction. Cardiovascular death was reduced by 15%, non-fatal MI by 28%, and non-fatal stroke by 7% (the stroke finding did not reach statistical significance individually, though the composite did).
Secondary outcomes included hospitalisations for heart failure (reduced), all-cause mortality, and atrial fibrillation. Body weight in the semaglutide group fell by approximately 9.4% versus 0.9% in the placebo group, a substantial but not dramatic difference relative to what has been seen in purely obesity-focused trials such as STEP-1.
The 20% MACE reduction in SELECT is larger than would be expected from a ~9% weight reduction alone. Modelling from prior cardiovascular risk studies suggests that a weight loss of that magnitude, achieved through dietary means, might reduce MACE risk by approximately 5–10% in high-risk populations. The SELECT signal appears to involve additional mechanisms.
GLP-1 receptors are expressed not only in the pancreas and hypothalamus but also in the heart, vasculature, and kidneys. Pre-clinical and human data suggest several direct cardioprotective pathways:
Anti-inflammatory effects. GLP-1 agonists reduce circulating levels of C-reactive protein (CRP), interleukin-6, and other inflammatory markers. In SELECT, reductions in CRP were observed independent of weight loss, suggesting direct anti-inflammatory signalling through the GLP-1 receptor pathway.
Endothelial function. GLP-1 receptor activation appears to improve endothelial nitric oxide bioavailability and reduce oxidative stress in vascular tissue. Animal models and small human studies have demonstrated improved flow-mediated dilation with GLP-1 agonist treatment, though large-scale data in humans remain limited.
Plaque stabilisation. There is emerging evidence, primarily from preclinical work and imaging substudies of outcomes trials, that GLP-1 agonists may reduce macrophage infiltration in atherosclerotic plaques and promote a more stable plaque phenotype. This remains an area of active investigation.
Renal protection. SELECT also demonstrated reductions in adverse kidney outcomes, including a composite of new macroalbuminuria, worsening eGFR, renal death, or kidney failure. Kidney disease is a major driver of cardiovascular risk, and the renoprotective signal provides an additional mechanistic pathway toward the MACE reduction observed.
Semaglutide in SELECT was associated with modest reductions in systolic blood pressure (approximately 3–4 mmHg) and small improvements in lipid profiles, including LDL-C reductions. While neither effect is large enough individually to account for a 20% MACE reduction, the combination of haemodynamic, metabolic, anti-inflammatory, and direct receptor-mediated effects likely compounds in ways that are difficult to attribute to any single pathway.
The weight loss itself also matters: adipose tissue is metabolically active and pro-inflammatory. A 9.4% reduction in body weight in a high-risk population produces clinically meaningful changes in visceral fat, insulin sensitivity, and sympathetic nervous system tone, all of which influence cardiovascular risk.
SELECT did not emerge in isolation. It sits within a body of cardiovascular outcomes trial (CVOT) evidence that has been building since 2016, when regulatory agencies began requiring cardiovascular safety data for all new diabetes medications.
The LEADER trial, published by Marso et al. in the New England Journal of Medicine (DOI: 10.1056/NEJMoa1603827), enrolled 9,340 adults with type 2 diabetes and high cardiovascular risk. Liraglutide reduced the primary MACE endpoint by 13% compared to placebo (HR 0.87, 95% CI 0.78–0.97; p=0.01 for superiority), with a 22% reduction in cardiovascular death driving much of the signal.
LEADER established that GLP-1 agonists could reduce cardiovascular events in diabetic populations. The key question it could not answer was whether the effect was mediated through glucose lowering, weight reduction, or direct GLP-1 receptor action.
The SUSTAIN-6 trial examined the same semaglutide molecule used in SELECT but in type 2 diabetes patients. It demonstrated a 26% reduction in MACE (HR 0.74, 95% CI 0.58–0.95; p<0.001 for non-inferiority; p=0.02 for superiority). Notably, the non-fatal stroke reduction was more prominent in SUSTAIN-6, raising questions about whether different populations respond differently across MACE components.
The REWIND trial extended the cardiovascular evidence base to dulaglutide, demonstrating a 12% MACE reduction in a type 2 diabetes population that included a higher proportion of patients with no prior cardiovascular event, closer to a primary prevention cohort. This trial reinforced the class effect while suggesting that GLP-1 cardiovascular benefit may extend beyond purely secondary prevention.
SELECT completes the mechanistic argument. If the cardiovascular benefit in LEADER, SUSTAIN-6, and REWIND were entirely mediated by glucose lowering, it should disappear in a non-diabetic population. It does not. SELECT confirms that the cardiovascular benefit of semaglutide is at least partially independent of HbA1c reduction, which transforms GLP-1 therapy from a diabetes-centric intervention to a genuinely cardiometabolic one.
At the time of writing, the Australian PBS landscape for GLP-1 therapy has been shaped primarily by diabetes and more recently by obesity indications. SELECT's findings have significant but not yet fully implemented clinical implications for Australian prescribers.
In Australia, semaglutide is listed on the PBS as:
The Wegovy dose used in SELECT is relevant here. That PBAC recommendation specifically targets severe obesity with established cardiovascular disease, the population SELECT studied, but until the listing takes effect most patients accessing Wegovy for obesity, with or without cardiovascular disease, pay the full private price. A patient with a prior MI, a BMI of 28, and no diabetes would not meet even the proposed criteria, which require a higher BMI threshold.
Australian cardiologists are increasingly incorporating SELECT data into clinical decision-making. The 2023 data prompted updates in international cardiovascular guidelines, with the American Heart Association and European Society of Cardiology both acknowledging GLP-1 agonists as agents with proven cardiovascular benefit in high-risk patients with obesity.
In practice, this means Australian cardiologists managing patients with established coronary artery disease, prior stroke, or peripheral vascular disease and coexisting obesity now have strong evidence-based grounds to consider semaglutide as part of a comprehensive secondary prevention strategy, alongside statins, antiplatelets, and blood pressure agents.
For understanding how GLP-1 receptor agonists produce these effects at a molecular and physiological level, the GLP-1 mechanism guide provides a detailed breakdown of receptor pharmacology, appetite signalling, and the distinction between pancreatic and extrapancreatic effects.
For patients who do not meet PBS criteria or cannot afford out-of-pocket branded costs (Wegovy without subsidy costs approximately $450–$550 per month in Australia), compounded semaglutide has been accessed through TGA-authorised compounding pharmacies under Special Access Scheme pathways. The implications and regulatory status of this access route are covered in the compounded semaglutide Australia access guide.
Researchers investigating the use of research-grade semaglutide peptides can find supply information at OzPeps Semaglutide 10mg.
Pharmaceutical Benefits Advisory Committee (PBAC) submissions typically lag trial evidence by several years. The SELECT data are likely to feature prominently in future PBAC discussions around expanding Wegovy PBS indications to include established cardiovascular disease as a standalone criterion, independent of BMI thresholds. Several Australian cardiologists and obesity specialists have made public submissions advocating for a cardiovascular indication that mirrors the SELECT population more precisely.
The SELECT trial produced evidence with direct implications for how Australian clinicians should approach the management of patients with obesity and cardiovascular disease:
Semaglutide reduces MACE in non-diabetic patients with established cardiovascular disease and overweight or obesity: a 20% reduction over approximately three years.
The benefit is not fully explained by weight loss alone. Anti-inflammatory, haemodynamic, and direct GLP-1 receptor-mediated mechanisms each contribute.
The evidence base is now multi-trial and multi-agent. LEADER, SUSTAIN-6, REWIND, and SELECT collectively demonstrate a cardiovascular class effect for GLP-1 agonists, with the strongest data for semaglutide specifically.
PBS access pathways exist via the Wegovy obesity listing for patients who meet BMI and comorbidity criteria, though a dedicated cardiovascular indication remains absent from current PBS schedules.
Cardiologists and GPs need to coordinate. SELECT data make GLP-1 therapy a secondary prevention consideration that crosses specialty boundaries, not just an endocrinology or weight loss question.
For a comparison of semaglutide and tirzepatide across efficacy, mechanism, and Australian access pathways, the tirzepatide vs semaglutide Australia comparison provides a detailed evidence-based breakdown.
The SELECT trial is a landmark study because it answers a question the earlier diabetes-based cardiovascular outcomes trials could not: does GLP-1 therapy protect the heart through mechanisms beyond glucose control? The evidence says yes. For Australian patients living with obesity and cardiovascular disease (a population that has historically fallen between the cracks of cardiology and endocrinology), the implications are substantial. Semaglutide is no longer a diabetes drug with cardiovascular benefits. It is a cardiometabolic agent that operates across weight, inflammation, vascular function, and renal protection simultaneously. How Australian PBS policy catches up with this evidence will determine which patients actually benefit.
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