Table 4.

Characteristics of most recent clinical trials on semaglutide.

Trial name, Author, Year	PIONEER 6, Husain et al. [149], 2019	STEP-HFpEF, Kosiborod et al. [146, 147, 148], 2023	SELECT, Lincoff et al. [150], 2023
Trial design	Event-driven, randomized, double-blind, placebo-controlled trial	Multinational (96 centers among 13 countries), double-blind, randomized, placebo-controlled clinical trial	Randomized, international multicenter, double-blind, placebo-controlled clinical trial
Study population	Patients with T2DM and:	Symptomatic patients with HFpEF (EF $\ge$45%), obesity (BMI $\ge$30 ${\mathrm{kg/m}}^2$) and without T2DM	Patients with overweight or obesity (BMI $\ge$ 27 ${\mathrm{kg/m}}^2$), established CVD (previous MI or stroke, or PAD) and without T2DM
	$\bullet$ $\ge$50 years old and CV disease or CKD, or
	$\bullet$ $\ge$60 years old and CV risk factors only
Intervention and control	Oral semaglutide (target dose, 14 mg) or placebo once-daily	Subcutaneous semaglutide (2.4 mg) or placebo once weekly	Subcutaneous semaglutide (2.4 mg) or placebo once weekly
Primary endpoint	$\bullet$ Time to the first occurrence of a MACE, a composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke	$\bullet$ Change in KCCQ -CSS from baseline (week 0) to end of treatment (week 52)	$\bullet$ Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-first-event analysis
		$\bullet$ Change in body weight (%) from baseline (week 0) to end of treatment (week 52)
Main secondary endpoints	Time to the first occurrence of the following: $\bullet$ an expanded composite outcome consisting of the primary outcome plus unstable angina resulting in hospitalization or HF resulting in hospitalization $\bullet$ a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke $\bullet$ the individual components of these composite outcomes	$\bullet$ Change in 6-MWD (meters) from baseline (week 0) to end of treatment (week 52) $\bullet$ Hierarchical composite of time to all-cause death from baseline (week 0) to end of study (week 57) $\bullet$ Hierarchical composite of number of HF events requiring hospitalization or urgent HF visit from baseline (week 0) to end of study (week 57) $\bullet$ Hierarchical composite of time to first HF event requiring hospitalization or urgent HF visit from baseline (week 0) to end of study (week 57) $\bullet$ Change in CRP (%) from baseline (week -2) to end of treatment (week 52)	Time-to-first-event analyses and tested in hierarchical order: $\bullet$ Death from cardiovascular causes; $\bullet$ A composite HF end point (death from cardiovascular causes or hospitalization or an urgent medical visit for HF); $\bullet$ Death from any cause. Additional endpoints: $\bullet$ Change in systolic blood pressure $\bullet$ Change in body weight
Number of patients enrolled	3183; semaglutide (n = 1591) or placebo (n = 1592)	529; semaglutide (n = 263) or placebo (n = 266)	17,604; semaglutide (n = 8803) or placebo (n = 8801)
Median duration of follow up	64 weeks	52 weeks	160 weeks
Main results	Primary endpoint (semaglutide vs. placebo): $\bullet$ MACEs: 3.8% vs. 4.8% (HR, 0.79; 95% CI, 0.57 to 1.11 p 0.001 for noninferiority) Secondary endpoints (semaglutide vs. placebo): $\bullet$ Death from CV causes: 0.9% vs. 1.9% (HR, 0.49; 95% CI, 0.27 to 0.92) $\bullet$ Nonfatal myocardial infarction: 2.3% vs. 1.9% (HR, 1.18; 95% CI, 0.73 to 1.90) $\bullet$ Nonfatal stroke: 0.8% vs. 1.0% (HR, 0.74; 95% CI, 0.35 to 1.57) $\bullet$ First events of HF resulting in hospitalization: 1.3% vs. 1.5% (HR, 0.86; 95% CI, 0.48 to 1.55) $\bullet$ Death from any cause: 1.4% vs. 2.8% (HR, 0.51; 95% CI, 0.31 to 0.84)	Co-primary endpoint (semaglutide vs. placebo): $\bullet$ Change in KCCQ-CSS: 16.6 vs. 8.7 (p 0.001) $\bullet$ Percentage change in body weight: –13.3 vs. –2.6 (p 0.001) Secondary endpoints (semaglutide vs. placebo): $\bullet$ Change in 6-MWD from baseline to week 52: 21.5 vs. 1.2 m (p 0.001) $\bullet$ Percentage reduction from baseline to week 52 in NT-proBNP: –20.9 vs. –5.3 (p 0.05) $\bullet$ Hospitalization or urgent visit for HF: 1 vs. 12 events (p 0.05) $\bullet$ Reduction in CRP levels at week 52: 43.5 vs. 7.3 (p 0.001) $\bullet$ Percentage reduction in NT-proBNP level at week 52: –20.9 vs. –5.3 $\bullet$ Adverse events were similar	Primary endpoint (semaglutide vs. placebo):
			$\bullet$ Composite of CV death, nonfatal MI, and nonfatal stroke, for semaglutide vs. placebo: 6.5% vs. 8.0% (HR 0.80, 95% CI 0.72–0.90, p 0.001)
			Secondary endpoints (semaglutide vs. placebo):
			$\bullet$ CV death: 2.5% vs. 3.0% (HR 0.85, 95% CI 0.71–1.01, p = 0.07)
			$\bullet$ HF composite end point: 3.4% vs. 4.1% (HR 0.82, 95% CI 0.71–0.96)
			$\bullet$ All-cause death: 4.3% vs. 5.2% (HR 0.81, 95% CI 0.71–0.93)
			$\bullet$ Nonfatal MI: 2.7% vs. 3.7% (HR 0.72, 95% CI 0.61–0.85)
			$\bullet$ Hospitalization or urgent medical visit for HF: 1.1% vs. 1.4% (HR 0.79, 95% CI 0.60–1.03)
			Additional endpoints:
			$\bullet$ Change in systolic blood pressure: –3.8 vs. –0.5 mm Hg
			$\bullet$ Mean change in body weight at 104 weeks: –9.4% vs. –0.9%

BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; CVD, cardiovascular disease; CKD, chronic kidney disease; HR, hazard ratio; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score; MACE, major cardiovascular event; MI, myocardial; HFpEF, heart failure with preserved ejection fraction; T2DM, type 2 diabetes mellitus; CV, cardiovascular; HF, heart failure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PAD, peripheral artery disease; EF, ejection fraction; 6-MWD, six minute walking test.