Table 1.

CVOTs and their results.

Trial	Drug	Subjects	Effect	References
ORIGIN	Insuline glargine	12,537 individuals with type 2 diabetes, impaired fasting glucose levels or impaired glucose tolerance, with additional risk factors for cardiovascular diseases (average baseline hemoglobin A1c level 6.5%)	No changes between the groups in either of the concomitant outcomes or in the individual components of the two coprimary outcomes. There were also no drastic changes in mortality or microvascular events	[49,50]
DEVOTE	Insuline glargine/Insulin degludec	7637 participants with an average baseline HbA1c level of 8.4%	Safety profile of insulin degludec for the cardiovascular system was comparable to the safety profile of insulin glargine U100. No cardinal differences were observed in the other prespecified CV results	[51]
RECORD	rosiglitazone	4447 participants with type 2 diabetes mellitus and an average baseline HbA1c level of 7.9%	MACE had no differences between test and control groups	[52]
PROactive	pioglitazone	5238 patients with type 2 diabetes, with extensive microvascular diseases	No significant differences between test and control groups (primary outcomes). However, during about three years of observation, an increase in the frequency of heart failure in the pioglitazone group compared with placebo was detected (11% vs. 8%, p < 0.0001).	[53]
IRIS	pioglitazone	Non-diabetic individuals with baseline HbA1c level 5.8%	Over 4.8 years of follow-up, there were considerably fewer cases of 3–P MACE when taking pioglitazone, in contrast to conventional treatment. Pioglitazone was able to considerably lower the incidence of DM2	[54]
EXAMINE	Alogliptin	5380 registered patients with type 2 diabetes following an acute coronary syndrome event	No important differences between the groups in both primary and cumulative CV outcomes. Secondary CV outcomes also did not show important differences between the test and placebo group.	[55]
SAVOR TIMI 53	Saxagliptin	16,490; the majority of participants already had cardiovascular diseases	No important differences between the groups in both primary and cumulative CV outcomes. Secondary CV outcomes also did not show important differences between the test and placebo group.The linkage of saxagliptin with noticeably elevated rates of hospitalization for heart failure compared to conventional medical care was found.	[56]
TECOS	Sitagliptin	14,671; the majority of participants already had cardiovascular diseases	No important differences between the groups in both primary and cumulative CV outcomes. Secondary CV outcomes also did not show important differences between the test and placebo groups.	[57]
CARMELINA	Linagliptin	6991 TDM2 patients	No important differences between test and control groups.	[58]
CAROLINA	Linagliptin/glimepiride	6033 TDM2 patients	Linagliptin was similar to glimepiride in all components of MAC	[59]
LEADER	liraglutide injection once a day	9341 patients with type 2 diabetes who were at high risk for cardiovascular disease	Noticeable reduction in the primary result of 3-P MACE, decrease in mortality from CVD, death from any cause, and MI	[60]
SUSTAIN-6	semaglutide for injection once a week	3297 patients with type 2 diabetes	Significantly fewer participants in the semaglutide group suffered a non-fatal stroke and revascularization of coronary or peripheral arteries	[61]
HARMONY	albiglutide injection once a week	9400 patients aged ≥40 years with T2DM, prior atherosclerotic CV disease, and suboptimal glycemic control	Albiglutide treatment led to a rather noticeable decrease in the frequency of 3P-MACE	[62]
REWIND	dulaglutide injection once a week	9901 type 2 diabetes patients who had either a previous cardiovascular event or cardiovascular risk factors	Decrease in the primary total result of 3P-MACE in the group receiving dulaglutide, compared to placebo	[63,64]
ELIXA	lixisenatide injection once a day	6068 participants with type 2 diabetes mellitus who experienced an acute coronary event within 180 days before recruitment	Lixisenatide demonstrated a neutral effect on all the primary and secondary endpoints	[65]
EXSCEL	exenatide injection once a week	14,752 participants	Exenatide showed a neutral effect on all secondary outcomes	[66]
PIONEER-6	daily oral semaglutide	3183 participants	Decrease in all-cause mortality and cardiovascular death	[67]
EMPA-REG OUTCOME	empagliflozin	7020 participants	Decreased mortality from all causes, CV mortality, hospitalization due to heart failure, and hospitalization due to insufficiency or death from CV causes (excluding fatal stroke)	[68]
CANVAS	canagliflozin	4330 participants	Marked decrease in 3P-MACE, canagliflozin reduced the number of hospitalizations due to heart failure	[69]
DECLARE-TIMI 58	dapagliflozin	17,160 participants	3P-MACE indicators had no significant discrepancies between dapagliflozin and the placebo; the frequency of hospitalization with heart failure was decreased with the use of dapagliflozin	[70]
VERTIS-CV	ertugliflozin	8246 patients	No noticeable effect of ertugliflozin in contrast to the placebo on 3P-MACE; fewer patients receiving ertugliflozin were hospitalized due to heart failure, in contrast to patients treated with placebo.	[71]