Novel pharmacological therapy in type 2 diabetes mellitus with established cardiovascular disease: Current evidence

Table 3 Summary of glucagon-like-peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors Randomized Controlled Trials

Trial	Number Follow up	CV disease (baseline)	Characteristics (baseline)	Drug vs Placebo (%) PEP	Superiority
ELIXA[22] (Lixisenatide) (2015)	n = 6068, 2.1 yr	Acute Coronary Events (previous 180 d)	Median age: 60; DM duration: 9.3 yr (median); A1c: 7.7%; BMI: 30.1	13.4 vs 13.2 (4-point MACE	No
LEADER[23] (Liraglutide) (2016)	n = 9340, 3.8 yr (median)	> 50 y/o + > 1 CV condition/CKD or Chronic HF or > 60 y/o > 1 risk factor for CVD	mean age: 64; DM duration: 12.8 yr (median); A1c: 8.7%; BMI: 32.5	13.0 vs 14.9	Yes
SUSTAIN-6[24] (Semaglutide) (2016)	n = 3297, 2.1 yr (median)	> 50 y/o + > 1 CV condition/CKD or Chronic HF or > 60 y/o > 1 CV condition	mean age: 65; DM duration: 13.9 yr (median); A1c: 8.7%; BMI: 30.1	6.6 vs 8.9	Yes
EXSCEL[26] (Exenatide) (2017)	n = 14752, 3.2 yr (median)	70% with previous CV events (CAD, ischemic cerebrovascular disease, or PAD)	mean age: 63; DM duration: 12 yr (median); A1c: 8.0%; BMI: 32	11.4 vs 12.2	No
REWIND (Dulaglutide) (2019)	?	?	?	?	?
EMPA-REG[31] (Empagliflozin) (2015)	n = 7020, 3.1 yr (median)	Established CV disease; high CV risk	mean age: 63; DM duration: > 10 yr 57%; 5-10 yr 25%; A1c: 8.07%; BMI: 30.6	10.5 vs 12.1	Yes
CANVAS[32] (Canagliflozin); ANVAS – R (Canagliflozin) (2017)	Total = 10142; CANVAS: n = 4330; CANVAS-R n = 5812; 3.6 yr (mean)	> 30 y/o at high CV risk (ASCVD) Or > 50 y/o > 2 CV risk factors	mean age: 63.3; DM duration: 13.5 yr (median); A1c: 8.2; %BMI: 32	9.8 vs 10.1	Yes
DECLARE[33] (Dapagliflozin) (2019)	n = 17160; 4.2 yr (median)	> 40 y/o established CVD or multiple risk factors	MEAN age: 64; DM duration: 11 yr (median); A1c: 8.3%; BMI: 32	8.8 vs 9.4	No

Not all the molecules currently available in the market have shown benefit for MACE. However, this can be explained by study design and/or random chance. More trials are needed to verify such findings. Note the CANVAS and CANVAS – R trials had to standardize their results to number of participants/1000 patient-yr. The results depicted in this table were converted to percentage. The REWIND trial results will become available on the ADA scientific meeting, 2019. The ELIXA trial had 4-point PEP that consisted in death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke or hospitalization for unstable angina. GLP-1 RA: Glucagon-like-peptide-1 receptor agonists; SGLT2i: Sodium glucose cotransporter 2 inhibitors; PEP: Primary end point; CV: Cardiovascular; MACE: Major cardiovascular events; CKD: Chronic kidney disease; CVD: Cardiovascular disease; HF: Heart failure; PAD: Peripheral artery disease; CAD: Coronary artery disease; ELIXA: Evaluation of Lixisenatide in acute coronary syndrome; LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6: Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; EXSCEL: Exenatide Study of Cardiovascular Event Lowering Trial; REWIND: Researching cardiovascular Events with a Weekly Incretin in Diabetes; EMPA-REG: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial; CANVAS: Canagliflozin Cardiovascular Assessment Study; CANVAS-R: A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus; DECLARE: Dapagliflozin Effect on Cardiovascular Events trial.