Prevention of macrovascular complications in patients with type 2 diabetes mellitus: Review of cardiovascular safety and efficacy of newer diabetes medications

Table 1 Summary of cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists

Drug	ELIXA	LEADER	SUSTAIN-6	EXSCEL
	Lixisenatide	Liraglutide	Semaglutide	Exenatide
Study design and salient features	Enrolled 6068 patients with T2DM and recent coronary event within 180 d; Median DM duration 9.2 yr; Median follow up 25 mo	Enrolled 9340 patients with T2DM and with high CV risks; Median DM duration 12.8 yr; Median follow up 3.8 yr	Enrolled 3297 patients with T2DM and established CV disease or with high CV risks; Median DM duration 13.2 yr and 14.1 yr in low dose and high dose treatment group, respectively; Median follow up 104 wk	Enrolled 14752 patients with T2DM at a wide range of CV risk; Approximately 27% of patients without known CV disease; Median DM duration 12 yr; Median follow up 3.2 yr; 43% subjects prematurely discontinued exenatide
Primary endpoint/MACE	No significant difference in MACE-4	13% reduction in MACE	26% reduction in MACE	9% reduction in MACE1
Secondary Outcomes	No significant difference in death from CV causes; No significant differences in rate of hospitalization for heart failure	22% reduction in death from CV causes2; 15% reduction in all-cause mortality2	39% reduction in nonfatal stroke; 26% reduction in nonfatal myocardial infarction3; No significant difference in CV death or all-cause mortality	14% reduction in all-cause mortality4; No significant differences in death from CV causes

¹Nonsignificant reduction (hazard ratio, 0.91; 95% confidence Interval, 0.83 to 1.00; P < 0.001 for noninferiority and P = 0.06 for superiority);

²Cardiovascular death and all-cause mortality benefits were apparent after 12-15 mo and 18 mo of liraglutide treatment, respectively;

³Nonsignificant reduction (hazard ratio, 0.74; 95% confidence interval, 0.51-1.08; P = 0.12);

⁴This difference was not considered to be statistically significant on the basis of the hierarchical testing plan. T2DM: Type 2 diabetes mellitus; DM: Diabetes mellitus; CV: Cardiovascular; MACE: Major adverse cardiovascular events, a composite of death from cardiovascular causes, non-fatal myocardial infarction, or nonfatal stroke; MACE-4: MACE endpoint as above and hospitalization for unstable angina.

Table 2 Summary of cardiovascular outcome trials of sodium-glucose cotransporter-2-inhibitors

Drug	EMPA-REG outcome	CANVAS	DECLARE-TIMI 58
	Empagliflozin	Canagliflozin	Dapagliflozin
Study Design and salient features	Enrolled 7028 patients with T2DM and established CV disease; 100% subjects with established CV disease; DM duration: 57% > 10 yr and 25.1% 5-10 yr; Median follow up 3.1 yr	Enrolled 9734 patients with T2DM and either established CV disease or high risk of CV disease; 65.6% subjects with established CV disease; Mean DM duration 13.5 yr; Mean follow up 188.2 wk	Enrolled 17160 patients with T2DM and with variable CV risks; 40.5% subjects with established CV disease; Median DM duration 11 yr; Median follow up of 4.2 yr
Primary endpoint/MACE	14% reduction in MACE in pooled empagliflozin group	14% reduction in MACE	No significant difference in MACE
Secondary Outcomes	35% reduction in hospitalization for heart failure1; 38% reduction in death from CV causes; 32% reduction in all-cause mortality	33% reduction in hospitalization for heart failure; No significant difference in death from CV causes; No significant difference in all-cause mortality	27% reduction in hospitalization for heart failure; No significant difference in death from CV causes; No significant difference in all-cause mortality

¹Heart failure hospitalization risk reduction results were similar in patients with and without CHF at baseline. T2DM: Type 2 diabetes mellitus; DM: Diabetes mellitus; CV: Cardiovascular; MACE: Major adverse cardiovascular events, a composite of death from cardiovascular causes, non-fatal myocardial infarction, or nonfatal stroke.