Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website https://www.cardiologyres.org

Review

Volume 15, Number 1, February 2024, pages 1-11

Pulse of Progress: A Systematic Review of Glucagon-Like Peptide-1 Receptor Agonists in Cardiovascular Health

**Table 1.** Summary of Head-to-Head Trials Comparing GLP-1 Agonists in A1c Lowering, Weight Reduction, and GI Side Effects
Trial	Drugs compared	Results of A1c lowering	Results of weight reduction	Results of GI side effects: nausea/vomiting/diarrhea
GLP-1: glucagon-like peptide-1; SC: subcutaneous; ER: extended release; GI: gastrointestinal.
LEAD-6 [5]	Liraglutide (1.8 mg SC daily)	1.12%	3.24 kg	25.5%/6.0%/12.3%
	Exenatide (10 µg SC twice daily)	0.79%	2.87 kg	28%/9.9%/12.1%
DURATION-6 [6]	Liraglutide (1.8 mg SC daily)	1.48%	3.57 kg	20.7%/10.7%/13.1%
	Exenatide ER (2.0 mg SC weekly)	1.28%	2.68 kg	9.3%/3.7%/6.1%
GETGOAL-X [7]	Lixisenatide (20 µg SC daily)	0.79%	2.96 kg	24.5%/10.1%/10.4%
	Exenatide ER (2.0 mg SC weekly)	0.96%	3.98 kg	35.1%/13.3%/13.3%
Trial by Nauck et al [8]	Liraglutide (1.8 mg SC daily)	1.8%	4.3 kg	21.8%/6.9%/12.4%
	Lixisenatide (20 µg SC daily)	1.20%	3.7 kg	21.8%/8.9%/9.9%
AWARD-1 [9]	Dulaglutide (1.5 mg SC weekly)	1.51%	1.3 kg	28%/16.8%/11.1%
	Dulaglutide (0.75 mg SC weekly)	1.30%	Gained 0.2 kg	16.1%/6.1%/7.9%
	Exenatide (10 µg SC twice daily)	0.99%	1.07 kg	25.7%/10.9%/5.8%
AWARD-6 [10]	Dulaglutide (1.5 mg SC weekly)	1.42%	2.9 kg	20.4%/7.0%/12.0%
	Liraglutide (1.8 mg SC daily)	1.36%	3.61 kg	18.0%/8.3%/12.0%
SUSTAIN-3 [11]	Semaglutide (1.0 mg SC weekly)	1.5%	5.6 kg	22.3%/7.2%/11.4%
	Exenatide ER (2.0 mg SC weekly)	0.90%	1.9 kg	11.9%/6.2%/8.4%
SUSTAIN-7 [12]	Semaglutide (0.5 mg SC weekly)	1.5%	4.6 kg	23%/10%/14%
	Semaglutide 1.0 mg SC weekly	1.8%	6.5 kg	21%/19%/14%
	Dulaglutide (0.75 mg SC weekly)	1.1%	2.3 kg	13%/4%/8%
	Dulaglutide (1.0 mg SC weekly)	1.4%	3.0 kg	20%/10%/18%
SUSTAIN-10 [13]	Semaglutide (1.0 mg SC weekly)	1.7%	5.8 kg	21.8%/10.4%/15.6%
	Liraglutide (1.2 mg SC daily)	1.0%	1.9 kg	15.7%/8%/12.2%
PIONEER-4 [14]	Semaglutide (14 mg oral daily)	1.2%	1.5 kg	20%/9%/15%
	Liraglutide (1.8 mg SC daily)	1.1%	0.9 kg	18%/5%/11%
PIONEER-10 [15]	Semaglutide (3 mg oral daily)	0.9%	0 kg	5%/2%/2%
	Semaglutide (7 mg oral daily)	1.4%	0.9 kg	8%/1%/2%
	Semaglutide (14 mg oral daily)	1.7%	1.6 kg	9%/7%/8%
	Dulaglutide (0.75 mg SC weekly)	1.4%	1.0 kg	9%/2%/6%
HARMONY-7 [16]	Albiglutide (30 - 50 mg SC weekly)	0.78%	N/A	Total: 35.9%
	Liraglutide (0.6 - 1.0 mg SC daily)	0.99%	N/A	Total: 49%
Rosenstock et al [17]	Efpeglenatide (0.3, 1.0, 2.0, 3.0, or 4.0 mg SC weekly)	0.56%, 0.95%, 1.19%, 1.41%, 1.61%	1.21 kg	11%/0/14%
			2.01 kg	8%/3%/3%
			1.52 kg	27%/12%/9%
			2.73 kg	22%/11%/11%
			3.31 kg	33%/22%/5%
	Liraglutide (1.8 mg SC daily)	1.38%	3.21 kg	33%/11%/14%
SURPASS-2 [18]	Tirzepatide (5 mg SC weekly)	2.01%	7.96 kg	17.4%/13.2%/5.7%
	Tirzepatide (10 mg SC weekly)	2.24%	9.3 kg	19.2%/16.4%/8.5%
	Tirzepatide (15 mg SC weekly)	2.30%	11.2 kg	22.1%/13.8%/9.8%
	Semaglutide (1 mg SC weekly)	1.86%	5.7 kg	17.9%/11.5%/8.3%
SURPASS J-MONO [19]	Tirzepatide (5 mg SC weekly)	2.4%	5.8 kg	12%
	Tirzepatide (10 mg SC weekly)	2.6%	8.5 kg	20%
	Tirzepatide (15 mg SC weekly)	2.8%	10.7 kg	20%
	Dulaglutide (0.75 mg SC weekly)	1.3%	0.5 kg	8%

Table 1. Summary of Head-to-Head Trials Comparing GLP-1 Agonists in A1c Lowering, Weight Reduction, and GI Side Effects

Trial

Drugs compared

Results of A1c lowering

Results of weight reduction

Results of GI side effects: nausea/vomiting/diarrhea

GLP-1: glucagon-like peptide-1; SC: subcutaneous; ER: extended release; GI: gastrointestinal.

LEAD-6 [5]

Liraglutide (1.8 mg SC daily)

1.12%

3.24 kg

25.5%/6.0%/12.3%

Exenatide (10 µg SC twice daily)

0.79%

2.87 kg

28%/9.9%/12.1%

DURATION-6 [6]

Liraglutide (1.8 mg SC daily)

1.48%

3.57 kg

20.7%/10.7%/13.1%

Exenatide ER (2.0 mg SC weekly)

1.28%

2.68 kg

9.3%/3.7%/6.1%

GETGOAL-X [7]

Lixisenatide (20 µg SC daily)

0.79%

2.96 kg

24.5%/10.1%/10.4%

Exenatide ER (2.0 mg SC weekly)

0.96%

3.98 kg

35.1%/13.3%/13.3%

Trial by Nauck et al [8]

Liraglutide (1.8 mg SC daily)

1.8%

4.3 kg

21.8%/6.9%/12.4%

Lixisenatide (20 µg SC daily)

1.20%

3.7 kg

21.8%/8.9%/9.9%

AWARD-1 [9]

Dulaglutide (1.5 mg SC weekly)

1.51%

1.3 kg

28%/16.8%/11.1%

Dulaglutide (0.75 mg SC weekly)

1.30%

Gained 0.2 kg

16.1%/6.1%/7.9%

Exenatide (10 µg SC twice daily)

0.99%

1.07 kg

25.7%/10.9%/5.8%

AWARD-6 [10]

Dulaglutide (1.5 mg SC weekly)

1.42%

2.9 kg

20.4%/7.0%/12.0%

Liraglutide (1.8 mg SC daily)

1.36%

3.61 kg

18.0%/8.3%/12.0%

SUSTAIN-3 [11]

Semaglutide (1.0 mg SC weekly)

1.5%

5.6 kg

22.3%/7.2%/11.4%

Exenatide ER (2.0 mg SC weekly)

0.90%

1.9 kg

11.9%/6.2%/8.4%

SUSTAIN-7 [12]

Semaglutide (0.5 mg SC weekly)

1.5%

4.6 kg

23%/10%/14%

Semaglutide 1.0 mg SC weekly

1.8%

6.5 kg

21%/19%/14%

Dulaglutide (0.75 mg SC weekly)

1.1%

2.3 kg

13%/4%/8%

Dulaglutide (1.0 mg SC weekly)

1.4%

3.0 kg

20%/10%/18%

SUSTAIN-10 [13]

Semaglutide (1.0 mg SC weekly)

1.7%

5.8 kg

21.8%/10.4%/15.6%

Liraglutide (1.2 mg SC daily)

1.0%

1.9 kg

15.7%/8%/12.2%

PIONEER-4 [14]

Semaglutide (14 mg oral daily)

1.2%

1.5 kg

20%/9%/15%

Liraglutide (1.8 mg SC daily)

1.1%

0.9 kg

18%/5%/11%

PIONEER-10 [15]

Semaglutide (3 mg oral daily)

0.9%

0 kg

5%/2%/2%

Semaglutide (7 mg oral daily)

1.4%

0.9 kg

8%/1%/2%

Semaglutide (14 mg oral daily)

1.7%

1.6 kg

9%/7%/8%

Dulaglutide (0.75 mg SC weekly)

1.4%

1.0 kg

9%/2%/6%

HARMONY-7 [16]

Albiglutide (30 - 50 mg SC weekly)

0.78%

N/A

Total: 35.9%

Liraglutide (0.6 - 1.0 mg SC daily)

0.99%

N/A

Total: 49%

Rosenstock et al [17]

Efpeglenatide (0.3, 1.0, 2.0, 3.0, or 4.0 mg SC weekly)

0.56%, 0.95%, 1.19%, 1.41%, 1.61%

1.21 kg

11%/0/14%

2.01 kg

8%/3%/3%

1.52 kg

27%/12%/9%

2.73 kg

22%/11%/11%

3.31 kg

33%/22%/5%

Liraglutide (1.8 mg SC daily)

1.38%

3.21 kg

33%/11%/14%

SURPASS-2 [18]

Tirzepatide (5 mg SC weekly)

2.01%

7.96 kg

17.4%/13.2%/5.7%

Tirzepatide (10 mg SC weekly)

2.24%

9.3 kg

19.2%/16.4%/8.5%

Tirzepatide (15 mg SC weekly)

2.30%

11.2 kg

22.1%/13.8%/9.8%

Semaglutide (1 mg SC weekly)

1.86%

5.7 kg

17.9%/11.5%/8.3%

SURPASS J-MONO [19]

Tirzepatide (5 mg SC weekly)

2.4%

5.8 kg

12%

Tirzepatide (10 mg SC weekly)

2.6%

8.5 kg

20%

Tirzepatide (15 mg SC weekly)

2.8%

10.7 kg

20%

Dulaglutide (0.75 mg SC weekly)

1.3%

0.5 kg

**Table 2.** Updated Ranking and Side Effects of GLP-1 Receptor Agonists When Comparing A1c Lowering and Weight Reduction
Drug (dose)	Within class comparability of A1c lowering efficacy	Within class comparability of effect on weight	Within class comparability of side effects
GLP-1: glucagon-like peptide-1; GI: gastrointestinal.SC: subcutaneous; ER: extended release; N/A: not available.
Albiglutide (30 - 50 mg SC weekly)	Lowest	N/A	Low
Exenatide (10 µg SC twice daily)	Lowest	Lowest	Highest
Lixisenatide (20 µg SC daily)	Lowest	Lowest	Intermediate
Exenatide ER (2.0 mg SC weekly)	Low	Lowest	Low
Dulaglutide (0.75 mg and 1.5 mg SC weekly)	Intermediate	Low	Intermediate/high
Liraglutide (1.8 mg SC daily)	Intermediate	Intermediate	Intermediate
Efpeglenatide (0.3, 1.0, 2.0, 3.0, or 4.0 mg SC weekly)	Intermediate	Intermediate	High
Semaglutide (0.5 mg and 1.0 mg SC weekly)	High	High	High
Semaglutide (7 mg and 14 mg oral daily)	High	High	Intermediate/high
Tirzepatide (5 mg, 10 mg, 15 mg SC weekly)	Highest	Highest	High

Table 2. Updated Ranking and Side Effects of GLP-1 Receptor Agonists When Comparing A1c Lowering and Weight Reduction

Drug (dose)

Within class comparability of A1c lowering efficacy

Within class comparability of effect on weight

Within class comparability of side effects

GLP-1: glucagon-like peptide-1; GI: gastrointestinal.SC: subcutaneous; ER: extended release; N/A: not available.

Albiglutide (30 - 50 mg SC weekly)

Lowest

N/A

Low

Exenatide (10 µg SC twice daily)

Lowest

Highest

Lixisenatide (20 µg SC daily)

Lowest

Intermediate

Exenatide ER (2.0 mg SC weekly)

Low

Lowest

Low

Dulaglutide (0.75 mg and 1.5 mg SC weekly)

Intermediate

Low

Intermediate/high

Liraglutide (1.8 mg SC daily)

Intermediate

Efpeglenatide (0.3, 1.0, 2.0, 3.0, or 4.0 mg SC weekly)

Intermediate

High

Semaglutide (0.5 mg and 1.0 mg SC weekly)

High

Semaglutide (7 mg and 14 mg oral daily)

High

Intermediate/high

Tirzepatide (5 mg, 10 mg, 15 mg SC weekly)

Highest

High

**Table 3.** Results of Head-to-Head Trials When Comparing CV Outcomes in GLP-1 Receptor Agonists
Trial	Drug (dose) vs. placebo	Results in CV outcome reduction (CV death/nonfatal MI/nonfatal stroke)	P value	Results of side effects that were significant
CV: cardiovascular; GLP-1: glucagon-like peptide-1; GI: gastrointestinal.SC: subcutaneous; ER: extended release; N/A: not available, bpm: beat per minute; HFpEF: heart failure with preserved ejection fraction.
ELIXA [20]	Lixisenatide (10 µg SC daily)	21%/62.8%/13.3%	0.81	N/A
	Placebo	23.3%/61.9%/12.3%
EXSCEL [21]	Exenatide ER (2.0 mg SC weekly)	4.6%/6.6%/2.5%	0.06	Increased HR by 2.51 bpm
	Placebo	7.9%/6.7%/2.9%
HARMONY [22]	Albiglutide (30 - 50 mg)	7%	P < 0.0006	None were significant.
	Placebo	9%
AMPLITUDE [23]	Efpeglenatide (4 or 6 mg SC weekly)	7%	P = 0.007	Increased GI side effects (constipation, diarrhea, nausea, vomiting, bloating)
	Placebo	9.20%		Significantly fewer decreases in kidney function
REWIND [24]	Dulaglutide (1.5 mg SC weekly)	12%	P = 0.026	Increased GI side effects
	Placebo	13.40%
LEADER [25]	Liraglutide (1.8 mg SC weekly)	13%	P = 0.01	Decreased incidence of renal or retinal microvascular events
	Placebo	14.90%
SUSTAIN-6 [26]	Semaglutide (0.5 and 1.0 mg SC weekly)	6.60%	P = 0.02	Increased incidence of retinopathy
				Decreased incidence of new or worsening nephropathy
	Placebo	8.90%		Decreased blood pressure by 2.6 mm Hg
PIONEER-6 [27]	Semaglutide (14 mg oral daily)	0.9%/2,3%/0.8%	P < 0.001	Increased GI side effects
	Placebo	1.9%/1.9%/1.0%
SELECT [28]	Semaglutide (2.4 mg SC weekly)	6.50%	P < 0.001	Increased incidence of gallbladder disorders
	Placebo	8%
STEP HFPEF [29]	Semaglutide (2.4 mg SC weekly)	+7.8 difference in KCCQ-CSS score, +20.3 m difference in 6-min walk distance change	P < 0.001	Improved symptom and physical limitations in HFpEF
	Placebo

Table 3. Results of Head-to-Head Trials When Comparing CV Outcomes in GLP-1 Receptor Agonists

Trial

Drug (dose) vs. placebo

Results in CV outcome reduction (CV death/nonfatal MI/nonfatal stroke)

P value

Results of side effects that were significant

CV: cardiovascular; GLP-1: glucagon-like peptide-1; GI: gastrointestinal.SC: subcutaneous; ER: extended release; N/A: not available, bpm: beat per minute; HFpEF: heart failure with preserved ejection fraction.

ELIXA [20]

Lixisenatide (10 µg SC daily)

21%/62.8%/13.3%

0.81

N/A

Placebo

23.3%/61.9%/12.3%

EXSCEL [21]

Exenatide ER (2.0 mg SC weekly)

4.6%/6.6%/2.5%

0.06

Increased HR by 2.51 bpm

Placebo

7.9%/6.7%/2.9%

HARMONY [22]

Albiglutide (30 - 50 mg)

P < 0.0006

None were significant.

Placebo

AMPLITUDE [23]

Efpeglenatide (4 or 6 mg SC weekly)

P = 0.007

Increased GI side effects (constipation, diarrhea, nausea, vomiting, bloating)

Placebo

9.20%

Significantly fewer decreases in kidney function

REWIND [24]

Dulaglutide (1.5 mg SC weekly)

12%

P = 0.026

Increased GI side effects

Placebo

13.40%

LEADER [25]

Liraglutide (1.8 mg SC weekly)

13%

P = 0.01

Decreased incidence of renal or retinal microvascular events

Placebo

14.90%

SUSTAIN-6 [26]

Semaglutide (0.5 and 1.0 mg SC weekly)

6.60%

P = 0.02

Increased incidence of retinopathy

Decreased incidence of new or worsening nephropathy

Placebo

8.90%

Decreased blood pressure by 2.6 mm Hg

PIONEER-6 [27]

Semaglutide (14 mg oral daily)

0.9%/2,3%/0.8%

P < 0.001

Increased GI side effects

Placebo

1.9%/1.9%/1.0%

SELECT [28]

Semaglutide (2.4 mg SC weekly)

6.50%

P < 0.001

Increased incidence of gallbladder disorders

Placebo

STEP HFPEF [29]

Semaglutide (2.4 mg SC weekly)

+7.8 difference in KCCQ-CSS score, +20.3 m difference in 6-min walk distance change

P < 0.001

Improved symptom and physical limitations in HFpEF

Placebo

**Table 4.** Ranking of GLP-1 Receptor Agonists When Comparing CV Outcomes
Drug (dose)	Within class comparability of A1c lowering efficacy	Within class comparability of effect on weight	Within class comparability of cardiovascular safety/efficacy	Strengths and weaknesses
CV: cardiovascular; GLP-1: glucagon-like peptide-1; GI: gastrointestinal.SC: subcutaneous; ER: extended release; HFpEF: heart failure with preserved ejection fraction; BP: blood pressure.
Albiglutide (30 - 50 mg)	Lowest	Unknown	High	Poor glycemic control
Exenatide (10 µg SC twice daily)	Lowest	Lowest	Unknown
Lixisenatide (10 µg SC daily)	Lowest	Lowest	Lowest	No significant difference from placebo
Exenatide ER (2.0 mg SC weekly)	Low	Lowest	Lowest	No significant difference from placebo
Dulaglutide (1.5 mg SC weekly)	Intermediate	Low	Intermediate	Renal benefit
				Increased GI side effects
Liraglutide (1.8 mg SC weekly)	Intermediate	Intermediate	Intermediate	Renal benefit BP lowering
Efpeglenatide (4 mg or 6 mg SC weekly)	Intermediate	Intermediate	High	Renal benefit
Semaglutide (14 mg oral daily)	High	High	Low	Increased GI side effects
Semaglutide (0.5 mg and 1.0 mg SC weekly)	High	High	Intermediate	Renal benefits, BP lowering
				Increased retinopathy
				Increased GI side effects
Semaglutide (2.4 mg SC weekly)	Highest	Highest	High	HFpEF benefits
				Increased incidence of gallbladder disorders
Tirzepatide	Highest	Highest	Unknown	No studies completed yet

Table 4. Ranking of GLP-1 Receptor Agonists When Comparing CV Outcomes

Drug (dose)

Within class comparability of A1c lowering efficacy

Within class comparability of effect on weight

Within class comparability of cardiovascular safety/efficacy

Strengths and weaknesses

CV: cardiovascular; GLP-1: glucagon-like peptide-1; GI: gastrointestinal.SC: subcutaneous; ER: extended release; HFpEF: heart failure with preserved ejection fraction; BP: blood pressure.

Albiglutide (30 - 50 mg)

Lowest

Unknown

High

Poor glycemic control

Exenatide (10 µg SC twice daily)

Lowest

Unknown

Lixisenatide (10 µg SC daily)

Lowest

No significant difference from placebo

Exenatide ER (2.0 mg SC weekly)

Low

Lowest

No significant difference from placebo

Dulaglutide (1.5 mg SC weekly)

Intermediate

Low

Intermediate

Renal benefit

Increased GI side effects

Liraglutide (1.8 mg SC weekly)

Intermediate

Renal benefit BP lowering

Efpeglenatide (4 mg or 6 mg SC weekly)

Intermediate

High

Renal benefit

Semaglutide (14 mg oral daily)

High

Low

Increased GI side effects

Semaglutide (0.5 mg and 1.0 mg SC weekly)

High

Intermediate

Renal benefits, BP lowering

Increased retinopathy

Increased GI side effects

Semaglutide (2.4 mg SC weekly)

Highest

High

HFpEF benefits

Increased incidence of gallbladder disorders

Tirzepatide

Highest

Unknown

No studies completed yet

**Table 5.** Anticipated Trials of GLP-1 Agonists
Trial (expected year of completion)	Objective
GLP-1: glucagon-like peptide-1.
SOUL (2025)	Semaglutide’s efficacy in reducing cardiovascular outcomes in those with atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD).
SURPASS-CVOT (2024)	Tirzepatide compared to dulaglutide in individuals with type 2 diabetes and established (ASCVD).
SUMMIT (2024)	Tirzepatide versus placebo in patients with heart failure with preserved ejection fraction and obesity.

Table 5. Anticipated Trials of GLP-1 Agonists

Trial (expected year of completion)

Objective

GLP-1: glucagon-like peptide-1.

SOUL (2025)

Semaglutide’s efficacy in reducing cardiovascular outcomes in those with atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD).

SURPASS-CVOT (2024)

Tirzepatide compared to dulaglutide in individuals with type 2 diabetes and established (ASCVD).

SUMMIT (2024)

Tirzepatide versus placebo in patients with heart failure with preserved ejection fraction and obesity.