Antidiabetic combination therapy and cardiovascular outcomes: An evidence-based approach

Table 1 Data from major cardiovascular outcome trials with glucagon-like polypeptide-1 receptor agonists

Trial name (n)	Drug vs comparator	Mean difference in HbA1c (%) (95%CI)	Mean difference in body weight in kg (95%CI)	CV outcome HR (95%CI)	Effect on MACE (non-inferior vs superior)
EXSCEL (n = 14752)[18]	Exenatide once weekly vs placebo	-0.53 (-0.57 to -0.50)	-1.27 (-1.4 to -1.13)	3-point MACE: 0.91 (0.83 to 1); P < 0.001 for non-inferior and P = 0.06 for superior	Non-inferior
ELIXA (n = 6068)[19]	Lixisenatide vs placebo	-0.27 (-0.31 to -0.22)	-0.70 (-0.9 to -0.5)	4-point MACE: 1.02 (0.89 to 1.17); P < 0.001 for non-inferior and P = 0.81 for superior	Non-inferior (likely failure to achieve superiority due to suboptimal GLP1 inhibition because of once a day dosing of lixisenatide despite being a short acting GLP1RA, and history of recent acute coronary event in all study participants)
LEADER (n = 9340)[20]	Liraglutide vs placebo	-0.40 (-0.45 to -0.34)	-2.30 (-2.5 to -2)	3-point MACE: 0.87 (0.78 to 0.97); P < 0.001 for non-inferior and P = 0.01 for superior	Superior. Reduced CV death
REWIND (n = 9901)[21]	Dulaglutide vs placebo	-0.61 (-0.65 to -0.58)	-1.46 (-1.67 to -1.25)	3-point MACE: 0.88 (0.79 to 0.99); P = 0.026 for superiority	Superior. Reduced non-fatal stroke and microvascular complications
HARMONY OUTCOMES (n = 9463)[22]	Albiglutide vs placebo	-0.52 (-0.58 to -0.45)	-0.83 (-1.06 to -0.6)	3-point MACE: 0.78 (0.68 to 0.90); P < 0·0001 for non-inferior and P = 0·0006 for superior	Superior. Reduced non-fatal MI
SUSTAIN-6 (n = 3297)[23]	Semaglutide s.c. vs placebo	-0.7 (-0.80 to -0.52) for 0.5 mg/week dose	-2.90 (-3.47 to -2.28) for 0.5 mg/week dose	3-point MACE: 0.74 (0.58 to 0.95); P < 0.001 for non-inferior; P = 0.02 for superior	Superior (as per posthoc analysis). Reduced non-fatal stroke; Worse retinopathy 1.76 (1.11 to 2.78; P = 0.02); No worse/new nephropathy
		-1 (-1.19 to -0.91) for 1 mg/week dose	-4.30 (-4.94 to -3.75) for 1 mg/week dose
PIONEER-6 (n = 3183)[24]	Semaglutide oral vs placebo	-0.7 (-0.42 to -1.26)	-3.40 (-4.20 to -2.30)	3-point MACE: 0.79 (0.57 to 1.11); P < 0.001 for non-inferior	Non-inferior. Reduced CV death

CVOTs: Cardiovascular outcome trials; GLP1RA: Glucagon-like polypeptide-1 receptor agonists; MACE: Major adverse cardiovascular events; GLP1: Glucagon-like polypeptide-1; CV: Cardiovascular; HR: Hazard ratio; CI: Confidence interval.

Table 2 Data from major cardiovascular outcome trials with sodium-glucose co-transporter 2 inhibitor

Trial name (n)	Drug vs comparator	Baseline CVD or risk factors (%)	Mean difference in HbA1c (%) (95%CI)	Mean difference in body weight in kg (95%CI)	Primary outcome HR (95%CI)	Hospitalization for heart failure HR (95%CI)	Composite CV death or heart failure hospitalization HR (95%CI)
CANVAS (n = 10142)[31]	Canagliflozin vs placebo	ASCVD (66); CAD (56); Stroke/CVD (19); HF (14.4)	-0.58 (-0.61 to -0.56)	-1.6 (-1.70 to -1.51)	3-point MACE: 0.86 (0.75 to 0.97); P < 0.001 for non-inferior; P = 0.02 for superior	0.67 (0.52 to 0.87)	0.78 (0.67 to 0.91). Amputation risk at the toe and metatarsal level
DECLARE-TIMI (n = 17160)[32,33]	Dapagliflozin vs placebo	ASCVD (41); CAD (33); Prior MI (21); Stroke/CVD (7); HF (10)	-0.42 (-0.45 to -0.40)	-1.80 (-2.00 to -1.70)	3-point MACE: 0.93 (0.84-1.03); P < 0.001 for-non-inferior and P = 0.17 for superior	0.73 (0.61 to 0.88); P < 0.005	0.83 (0.73 to 0.95); P = 0.005 for superiority
EMPA-REG (n = 7020)[30]	Empagliflozin vs placebo	ASCVD (99); CAD (76); Prior MI (46); Stroke (23); HF (10)	-0.57 ( -0.70 to -0.43) for 10 mg	-1.63 (-2.11 to -1.5) for 10 mg	3-point MACE: 0.86 (0.74 to 0.99); P < 0.001 for non-inferior and 0.04 for superior	0.65 (0.5 to 0.85); P = 0.002	0.62 (0.49 to 0.77); P < 0.001
			-0.64 (-0.77 to -0.50) for 25 mg	-2.01 ( -2.49 to -1.53) for 25 mg
VERTIS-CV (n = 8246)[34]	Ertugliflozin vs placebo	ASCVD (100); CAD (76); Prior MI (48); Stroke/CVD (23); HF (24)	-0.70 (-0.90 to -0.50) for 5 mg	-3.00 (-3.30 to -2.70) for 5 mg	3-point MACE: 0.97 (0.85 to 1.11); P < 0.001 for noninferior	0.7 (0.54 to 0.9)	0.88 (0.75 to 1.03); P = 0.11 for superiority
			-0.90 (-1.00 to -0.70) for 15 mg	-2.90 (-3.20 to -2.60) for 15 mg
SCORED (n = 10584)[35]	Sotaglifozin vs placebo	ASCVD (89); Prior MI (19.9); Prior PCI (22.8); HF (31); Stroke (8.9)	-1.16 (-1.26 to -1.06)	-1.16 (-1.26 to -1.06)	Total number of deaths from CV causes, hospitalization for HF, and urgent visits for HF: 0.74 (0.63-0.88); P < 0.001	0.67 (0.55 to 0.82); P < 0.001	0.77 (0.66 to 0.91)

CVD: Cardiovascular disease; HbA1c: Glycated hemoglobin; CV: Cardiovascular; HR: Hazard ratio; CI: Confidence interval; ASCVD: Atherosclerotic cardiovascular disease; CAD: Coronary artery disease; HF: Heart failure; MACE: Major adverse cardiovascular events; MI: Myocardial infarction; PCI: Percutaneous coronary intervention.