From the SELECT study to SOUL: different administration methods of semaglutide but same efficacy?

Abstract

Semaglutide from subcutaneous to oral formulation in the treatment of type 2 diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs widely used for treating type 2 diabetes mellitus (T2DM) due to their ability to improve glycaemic status without the risk of hypoglycaemia. Endogenous GLP-1 is secreted by enteroendocrine L cells of the gastrointestinal tract and is responsible for enhancing glucose-induced insulin secretion in the postprandial period. GLP-1 RAs are synthetically modified peptides similar to endogenous GLP-1 and act on several organs (brain, pancreas, liver, heart, intestine, kidney, muscles, and vessels), causing numerous effects that include signals sent to the hypothalamus that reduce appetite, stimulate gluconeogenesis, limit hepatic glucose production, amplify glucose-dependent insulin release, inhibit glucagon release, and increase cardiac output and cardioprotection. GLP-1 RAs also slow gastric emptying and reduce blood pressure.¹

Semaglutide is a GLP-1 analogue shown in numerous clinical studies to be effective and safe in treating patients with T2DM in the subcutaneous formulation administered once a week.

The SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) programme, which has included 10 randomized trials for a total of over 10 000 diabetic patients, confirmed the efficacy of subcutaneous semaglutide both compared to placebo and to other hypoglycaemic agents belonging to the same or different pharmacological classes. For example, in the SUSTAIN 3 and SUSTAIN 7 studies, this drug determined superior glycaemic control and weight loss compared to two other GLP-1 RA analogues [exenatide and dulaglutide (P < 0.0001)].² In the SUSTAIN-6 study, conducted in 3297 patients with T2DM and cardiovascular and/or chronic kidney disease, subcutaneous semaglutide compared with placebo was associated with a 26% relative reduction and a 2.3% absolute reduction in the risk of major adverse cardiovascular events (MACE), a reduction driven by a significant decrease in the incidence of stroke (39%) and myocardial infarction (26%), but with no significant difference in the incidence of cardiovascular death.³

Semaglutide is also available in an oral formulation approved by the FDA in 2019 and assembled in a tablet with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino-caprylate (SNAC), which prevents its enzymatic degradation in the stomach by raising the pH, facilitating its absorption through inter-epithelial junctions and allowing its paracellular transport through the gastric mucosa. Once SNAC is incorporated into the gastric epithelium, it fluidifies the lipid membrane, facilitating the transport of semaglutide and entry into the systemic circulation. When semaglutide and SNAC reach the bloodstream, the two molecules promptly dissociate, allowing semaglutide to interact with its targets.⁴

The efficacy and safety of oral semaglutide have been tested in the PIONEER studies, a programme that has so far seen the completion of 10 randomized studies with enrolment of over 9500 patients. While the PIONEER 1 study documented the superiority of oral semaglutide in reducing body weight and glycated haemoglobin levels compared to diet and exercise in diabetic subjects, other studies have demonstrated the same superiority in comparison with other hypoglycaemic agents: vs. empagliflozin in PIONEER 2, vs. liraglutide in PIONEER 4, and vs. sitagliptin in PIONEER 5.² The PIONEER 6 study instead evaluated the safety of oral semaglutide in a population at high cardiovascular risk, enrolling 3183 subjects with T2DM aged ≥50 years with established cardiovascular and/or renal disease or aged >60 years with cardiovascular risk factors only. The event-driven study was stopped after only 20 months, demonstrating a significantly reduced incidence of MACE (cardiovascular death, myocardial infarction, and non-fatal stroke) in the semaglutide group compared to placebo (3.8% vs. 4.8%; P < 0.001). Furthermore, patients treated with semaglutide had fewer hospitalizations for unstable angina, a more significant reduction in body weight, and better blood pressure control.⁵

Semaglutide is generally well tolerated in the oral and subcutaneous formulations. The main side effects are related to slowed gastric emptying and are mainly represented by nausea, vomiting, diarrhoea, constipation, and abdominal pain. An even less common side effect is gallstones.

The benefits of semaglutide in the treatment of obese patients: from the STEP studies to the SELECT study

In 2021 and 2022, the US and European regulatory agencies approved the use of semaglutide administered subcutaneously at a dose of 2.4 mg once a week for the treatment of patients without diabetes but obese (body mass index, BMI > 30) or overweight but with at least one weight-related complication (hypertension, diabetes, dyslipidaemia, or obstructive sleep apnoea syndrome). This approval was supported by the results of the STEP (Semaglutide Treatment Effect in People with Obesity) programme, a set of trials conducted to demonstrate the safety, efficacy, and tolerability of this semaglutide regimen in patients with these specific phenotypes.

In all these studies, which globally enrolled over 10 000 patients, treatment with semaglutide administered subcutaneously once a week and compared with placebo or liraglutide was combined with a hypocaloric diet and a progressively increasing intensity of physical activity. While the primary endpoint was generally represented by the percentage change in body weight at the end of treatment compared to baseline, secondary endpoints included the percentage of patients who achieved a weight loss of at least 10%, 15%, or 20%, and the change in control of the main cardiovascular risk factors and obesity-related comorbidities. All STEP studies achieved the primary endpoint with a reduction in body weight ranging from −6.2% in STEP 2 to −12.4% in STEP 1 and −12.6% in STEP 5.⁶ In further support of these important results, the STEP 8 study, which compared semaglutide head-to-head with liraglutide (the first GLP-1RA to be approved for the treatment of obesity), also achieved the primary endpoint by demonstrating significantly more significant weight loss in the semaglutide group, with a difference in weight from baseline of −9.4%, and a more significant number of subjects who achieved a weight loss of at least 10%, 15%, and 20% at the end of the trial.⁷ As for secondary endpoints, it is important to underline that in all studies, treatment with semaglutide resulted in a significant improvement in cardiovascular risk factors with a significant reduction in waist circumference and blood pressure values and a significant increase in the percentage of subjects who passed from a state of pre-diabetes to that of euglycaemia. The results of the STEP studies also demonstrate how semaglutide improved the lipid profile of these patients, with a significant reduction in total cholesterol, LDL, and triglycerides and an increase in HDL cholesterol compared to placebo.⁶

More recently, the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial definitively confirmed the efficacy of semaglutide in secondary cardiovascular prevention in overweight/obese, non-diabetic patients. A total of 17 604 patients were randomized to receive 2.4 mg of subcutaneous semaglutide once weekly or placebo. Eligible subjects were those with an age ≥ 45 years, a BMI ≥ 27, and a confirmed diagnosis of cardiovascular disease defined by one or more of the following conditions: previous myocardial infarction, previous ischaemic or haemorrhagic stroke, and symptomatic peripheral arterial disease (intermittent claudication with an ankle-brachial index < 0.85, previous peripheral arterial revascularization procedure, previous amputation due to atherosclerotic disease). Patients were excluded if they had glycated haemoglobin levels > 6.5%, diabetes, if they were treated with oral hypoglycaemic agents or GLP1-RAs in the 90 days prior to randomization, and if they had NYHA class IV heart failure or end-stage renal disease. Patients could not be enrolled within 60 days of a cardiovascular or neurological event or if they were scheduled for coronary, carotid, or peripheral revascularization. The study’s primary endpoint was MACE; secondary endpoints included the time from randomization to the occurrence of cardiovascular death, all-cause death, and first heart failure event evaluated hierarchically. The mean age of the population was 61.6 years, with over 70% of subjects being male, a state of pre-diabetes (glycated haemoglobin levels between 5.7% and 6.4%) was present in 64.5% of cases, while the mean BMI was 33.3, with over 71% of the population classified as obese. More than three-quarters of patients reported a history of previous myocardial infarction, and almost a quarter had chronic heart failure. A cardiovascular event occurred in 569 patients (6.5%) of the semaglutide group and in 701 patients (8.0%) of the placebo group (P < 0.001). Death from cardiovascular causes, the first confirmatory secondary endpoint, occurred in 223 patients (2.5%) of the semaglutide group and 262 patients (3.0%) of the placebo group. Since the difference between the groups did not reach statistical significance, the other secondary endpoints were not evaluated. The SELECT study nevertheless demonstrated that the use of semaglutide compared to placebo reduces the risk of cardiovascular death, myocardial infarction, and stroke by 20%, with also a significant reduction in body weight (up to −9.39%) and waist circumference (up to −7.56 cm).⁸

The exact mechanism by which semaglutide reduces cardiovascular risk is not fully understood. However, several hypotheses have been formulated related to the physiological benefits resulting from the reduction of excess abnormal body fat and to actions of this drug other than weight loss. Weight reduction results not only in improvements in glucose levels and traditional cardiovascular risk factors but also in a decrease in ectopic adipose tissue deposits (perivascular and epicardial) that may contribute to atherosclerosis and myocardial dysfunction by exerting direct adverse effects on the vascular endothelium.⁹ Furthermore, reducing excess abnormal body fat improves the systemic pro-inflammatory and prothrombotic state associated with obesity.¹⁰

The efficacy of semaglutide in chronic kidney disease: the FLOW study

The FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial is a multicentre, randomized, double-blind, placebo-controlled study that enrolled patients with T2DM and high-risk chronic kidney disease defined by an estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m² (with a urinary albumin/creatinine ratio between 300 and 5000 if eGFR ≥ 50 mL/min/1.73 m² or with a urinary albumin/creatinine ratio between 100 and 5000 if eGFR > 25 and <50 mL/min/1.73 m²).

The primary endpoint of the study was a major renal event, defined as the composite of end-stage renal disease (initiation of long-term dialysis, kidney transplantation, or eGFR decline to <15 mL/min/1.73 m² for at least 28 days), sustained (for ≥28 days) eGFR decline of at least 50% from baseline, and death from renal or cardiovascular causes. Three hierarchically assessed secondary endpoints were also considered: overall eGFR slope (defined as the annual rate of change in eGFR from randomization to the end of the study), MACE (myocardial infarction, stroke, cardiovascular death), and death from any cause.

The final population included 3533 patients: 1767 were randomized to semaglutide, and 1766 were randomized to placebo, with a mean age of 66 years and 30% women. The mean eGFR was 47.0 mL/min/1.73 m², the mean urinary albumin-to-creatinine ratio was 567, 22% had a history of previous heart attack or stroke, and 19% had heart failure.

In October 2023, after 570 events, an interim analysis was performed, after which the study was stopped early for efficacy. The primary endpoint occurred less frequently in the semaglutide group than in the placebo group: 331 vs. 410, with a relative risk reduction of 24% (HR 0.76; P = 0.0003) and with a three-year number needed to treat (NNT) of 20. Semaglutide also had a lower risk for the composite of renal components of the primary endpoint (HR 0.79) and cardiovascular death (HR 0.71). Benefits were observed for all three hierarchically tested secondary endpoints, with the semaglutide group demonstrating, compared to placebo, a slower decline in eGFR (−2.19 vs. −3.36 mL/min/1.73 m² per year; P < 0.001), an 18% lower risk of MACE (212 vs. 254 events; HR 0.82; 95% CI, P = 0.029), and a 20% lower risk of death from any cause (227 vs. 279 events; HR 0.80; P = 0.01), with a three-year NNT of 45 for the prevention of a cardiovascular event and 39 for the prevention of a death from any cause.¹¹ The renal protection mechanism demonstrated by semaglutide is multifactorial. Although improving some risk factors, such as diabetes and hypertension, may contribute to the observed benefit, previous evidence has shown that this effect on renal protection is very modest. Based on experimental models and biomarker data, the direct effect of GLP-1RAs on the kidney has been demonstrated, and it may include the reduction of inflammation, oxidative stress, and fibrosis. Both intrinsic renal cells and immune cells express the GLP-1 receptor, and agonists can act locally by inhibiting the cellular expression of pro-inflammatory and pro-fibrotic mediators.¹²

Latest evidence on the benefit of oral semaglutide in diabetic patients at high cardiovascular risk: the SOUL study

The SOUL study (Semaglutide cardiOvascular oUtcomes triaL) is a randomized, double-blind study comparing oral semaglutide vs. placebo in addition to standard therapy in patients with T2DM and concomitant diagnosis of cardiovascular or chronic kidney disease defined by the presence of at least one of the following conditions:

• Coronary artery disease (previous myocardial infarction, previous coronary revascularization, stenosis ≥ 50% in at least one coronary artery documented by coronary angiography or coronary CT, myocardial ischaemia documented by stress imaging);

• Cerebrovascular disease (previous stroke, previous carotid revascularization, stenosis ≥ 50% in the carotid artery documented by angiography, MRI, CT, or Doppler ultrasound);

• Symptomatic peripheral arterial disease (intermittent claudication with ankle-brachial index < 0.85 at rest or with ≥50% stenosis in ≥1 peripheral artery documented by angiography, MRI, CT, or Doppler ultrasound, prior peripheral artery revascularization, lower limb amputation at or above the ankle for atherosclerotic disease); and

• Chronic kidney disease (eGFR < 60 mL/min/1.73 m²).

The main exclusion criteria were: acute myocardial infarction or stroke, transient ischaemic attack, or hospitalization for unstable angina within 60 days prior to randomization, planned coronary, carotid, or peripheral artery revascularization, NYHA class IV heart failure, treatment with any GLP-1RA within 30 days, end-stage renal disease on haemodialysis, major gastric surgery, and uncontrolled diabetic retinopathy or maculopathy.

The primary endpoint of the study was the time from randomization to the first MACE (cardiovascular death, myocardial infarction, or non-fatal stroke). Secondary endpoints included time from randomization:

• To the occurrence of the first event in the composite of cardiovascular death, death from renal disease, persistent ≥50% decline from baseline in eGFR, persistently <15 mL/min/1.73 m² eGFR, initiation of chronic renal replacement therapy (dialysis or kidney transplant);

• To death from cardiovascular causes; and

• To the occurrence of the first event related to limb ischaemia (acute or chronic).

SOUL was an event-driven trial conducted until 1225 primary endpoint events occurred. Between 2019 and 2021, 9650 patients were randomized to receive oral semaglutide or placebo. To date, the characteristics of the population are known: most participants were male (71.1%) and white (68.9%), with a mean age of 66.1 years and a BMI of 31.1 kg/m². The mean levels of glycated haemoglobin were 8.0%. Many participants reported hypertension (90.7%) treated with at least one antihypertensive drug; almost a third (29.1%) had an eGFR < 60 mL/min/1.73 m² at baseline. Much of the population had a history of coronary artery disease (70.7%), while 21.1% had cerebrovascular disease, 15.7% had symptomatic arterial disease, and 42.3% had chronic kidney disease (diagnoses not mutually exclusive).¹³

The study’s results will be presented during the annual meeting of the American College of Cardiology (Chicago 29–31 March 2025). However, NovoNordisk has announced that the trial met its primary endpoint and that in this setting, oral semaglutide reduces the primary composite endpoint of cardiovascular death, non-fatal heart attack, and stroke by 14% compared to standard therapy.

The new European Society of Cardiology guidelines

During the last Congress of the European Society of Cardiology, the new guidelines on Chronic Coronary Syndromes were released, where GLP-1 RAs, due to the enormous cardiovascular benefit demonstrated, are considered among the first-choice drugs for the treatment of diabetes mellitus, regardless of baseline or desired levels of glycated haemoglobin and the concomitant use of other hypoglycaemic agents (class I, level of evidence A). Furthermore, considering the results of the SELECT study, the use of semaglutide is recommended in patients with chronic ischaemic heart disease without diabetes but with overweight or obesity (BMI > 27 kg/m²) to reduce the risk of cardiovascular death, heart attack, and stroke (class IIa, level of evidence B).¹⁴

Funding

No funding provided.

Data availability

No new data were generated or analysed in support of this research.

Disclaimer

This paper was originally published in the Italian language as ‘Dallo studio Select al Soul: diverse modalità di somministrazione della semaglutide ma stessa efficacia?’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2025”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.

References

Author notes