Glucagon-like peptide-1 receptor agonists in type 2 diabetes: Evidence for disease modification and therapeutic switching

Table 1 Summary of findings from the cardiovascular outcome trials with glucagon-like peptide-1 receptor agonists[16,27-29,52-54]

	EXSCEL[27]	ELIXA[28]	LEADER[29]	REWIND[30]	HARMONY[31]	SUSTAIN-6[32]	PIONEER-6[33]
Intervention	Exenatide once weekly subcutaneous vs placebo	Once-daily subcutaneous lixisenatide vs placebo	Once daily subcutaneous liraglutide vs placebo	Weekly subcutaneous dulaglutide vs placebo	Weekly subcutaneous albiglutide vs placebo	Once-weekly subcutaneous semaglutide vs placebo	Once-daily oral semaglutide vs placebo
Population (n)	14752	6068	9340	9901	9463	3297	3183
Established CV disease (%)	73.1	100	81.3	31.5	100	83	84.7
Follow-up period (years), (median IQR)	3.2 (2.2 to 4.4)	2.1	3.8	5.4	1.6 (1.3 to 2)	2.1	1.3
Mean/median HbA1c at baseline (%)	8	7.6	8.7	7.2	8.7	8.7	8.2
Mean difference in HbA1c (%), (95%CI)	-0.53 (-0.57 to -0.50)	-0.27 (-0.31 to -0.22)	-0.40 (-0.45 to -0.34)	-0.61 (-0.65 to -0.58)	-0.52 (-0.58 to -0.45)	-0.7 (-0.80 to -0.52) for a 0.5 mg/week dose-1 (-1.19 to -0.91) for a 1 mg/week dose	-0.7% (-0.42 to -1.26)
Mean difference in body weight (kg), (95%CI)	-1.27 (-1.4 to -1.13)	-0.7 (-0.9 to -0.5)	-2.3 (-2.5 to -2)	-1.46 (-1.67 to -1.25)	-0.83 (-1.06 to -0.6)	-2.9 (-3.47 to -2.28) for a 0.5 mg/week dose-4.3 (-4.94 to -3.75) for a 1 mg/week dose	-3.4 (-4.2 to -2.3)
Mean difference in systolic blood pressure (mmHg), (95%CI)	Not reported	−0.8 (-1.3 to -0.3)	-1.2 (-1.9 to 0.5)	-1·70 (-1.33 to -2.07)	–0.67 (-1.40 to 0.06)	-1.3 (P = 0.10) for 0.5 mg/week dose, -2.6 (P < 0.001) in 1.0 mg/week dose	-2.6 (-3.7 to -1.5)
Primary outcome, HR (95%CI)	3P-MACE, 0.91 (0.83 to 1.0) P < 0.001 for noninferiority, P = 0.06 for superiority	4P-MACE, 1.02 (0.89 to 1.17) P = 0.81	3P-MACE, 0.87 (0.78 to 0.97), P = 0.01 for superiority1	3P-MACE, 0.88 (0.79 to 0.99), P = 0.026 for superiority1	3P-MACE, 0.78 (0.68 to 0.90), P = 0.0006 for superiority1	3P-MACE, 0.74 (0.58 to 0.95), P = 0.02 for superiority1	3P-MACE, 0.79 (0.57 to 1.11)
Key secondary outcomes
CV death, HR (95%CI)	0.88 (0.76 to 1.02)	0.98 (0.78 to 1.22)	0.78 (0.66 to 0.93), P = 0.0071	0.91 (0.78 to 1.06)	0.93 (0.73 to 1.19)	0.98 (0.65 to 1.48)	0.49 (0.27 to 0.92)
All-cause mortality, HR (95%CI)	0.86 (0.77 to 0.97)	0.94 (0.78 to 1.13)	0.85 (0.74 to 0.97), P = 0.021	0.90 (0.80 to 1.01)	0.95 (0.79 to 1.16)	1.05 (0.74 to 1.50)	0.51 (0.31 to 0.84)
Non-fatal myocardial infarction, HR (95%CI)	0.97 (0.85 to 1.10)	1.03 (0.87 to 1.22), P = 0.71	0.86 (0.73 to 1.00), P = 0.0461	0.96 (0.79 to 1.15)	0.75 (0.61 to 0.90), P = 0.0031	0.74 (0.51 to 1.08)	1.18 (0.73 to 1.90)
Non-fatal stroke, HR (95%CI)	0.85 (0.70 to 1.03)	1.12 (0.79 to 1.58)	0.86 (0.71 to 1.06)	0.76 (0.62 to 0.94), P = 0.011	0.86 (0.66 to 1.14)	0.61 (0.38 to 0.99), P = 0.041	0.74 (0.35 to 1.57)
Hospitalization for HF, HR (95%CI)	0.94 (0.78 to 1.13)	0.96 (0.75 to 1.23)	0.87 (0.73 to 1.05)	0.93 (0.77 to 1.12)	0.85 (0.64 to 1.11)	1.11 (0.77 to 1.61)	0.86 (0.48 to 1.55)
Adverse effects	No clinically relevant between-group differences	Leading to discontinuation (11.4% vs 7.2%, P < 0.001). GI events (4.9% vs 1.2%), P < 0.0011	GI events were more frequent in the liraglutide group than in the placebo group. Acute gallstone disease (3.1% vs 1.9%), P < 0.0011. Pancreatic carcinoma (0.3% vs 0.1%), P = 0.061	GI events (47.4% vs 34.1%), P < 0.00011	Injection site reactions (2% vs 1%)	Retinopathy complications 1.76 (1.11 to 2.78), P = 0.021. GI disorders are more common in the semaglutide arms vs the placebo	Treatment discontinuation and GI events were more common in the semaglutide than the placebo group

¹Significant outcomes.

New or worsening nephropathy persistent macroalbuminuria, persistent doubling of the serum creatinine level and a creatinine clearance of less than 45 mL per minute per 1.73 m² of body-surface area (according to the modification of diet in renal disease criteria), or the need for continuous renal-replacement therapy. Retinopathy complications vitreous hemorrhage, onset of diabetes-related blindness, and the need for treatment with an intravitreal agent or retinal photocoagulation. CV: Cardiovascular; HR: Hazard ratio; HbA1c: Glycated hemoglobin; CI: Confidence interval; HF: Heart failure; IQR: Interquartile range; GI: Gastrointestinal; 3P-MACE: 3-point major adverse cardiovascular event; 4P-MACE: 4-point major adverse cardiovascular event.