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

Table 1 Summary of dipeptidyl peptidase 4 cardiovascular outcome trials

Trial	NumberFollow up	CVD (baseline)	Characteristics (baseline)	Drug vs Placebo (%) PEP	Superiority
SAVOR-TIMI53 (Saxagliptin) 2013	n = 16492, 2.1 yr (median)	Pre-existing CV or high CV risk/multiple CV risk factors	65 y/o, DM duration: 10 yr; A1c: 8%; BMI: 31	7.3 vs 7.2	No
EXAMINE (Alogliptin) 2013	n = 5380, 1.5 yr (median)	Acute MI or HUA in previous 15 to 90 d	61 y/o, DM duration: 7 yr; A1c: 8%; BMI: 29	11.3 vs 11.8	No
TECOS (Sitagliptin) 2015	n = 14671, 3.1 yr (median)	Pre-existing CV disease (CAD, ischemic stroke, PAD)	65.5 y.o, DM duration: 11.6 yr; A1c: 7.2%; BMI: 30.2	11.4 vs 11.6 (4-point MACE)	No

Note, as a class dipeptidyl peptidase 4 inhibitor has no data for significant reduction in cardiovascular endpoints. The TECOS trial had a 4-point MACE, consisting of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke or hospitalization for unstable angina. DPP4: Dipeptidyl peptidase 4; CVOT: Cardiovascular outcome trial; CVD: Cardiovascular disease; PEP: Primary end point; BMI: Body mass index; HUA: Hospitalization due to unstable angina; MI: Myocardial infarctions; PAD: Peripheral artery disease; CAD: Coronary artery disease; MACE: Major cardiovascular events.

Table 2 Summary of the results of the most important Randomized Controlled Trials prior to the new classes of antidiabetic medications

Study	Effects on microvascular complications	Effects on macrovascular complications	Effect on total mortality
DCCT[10] (1993), T1DM	Reduced retinopathy, nephropathy, neuropathy	No difference on major cardiovascular and peripheral vascular events	No difference
UKPDS[9] (1998)	Reduced microvascular endpoints	No difference on myocardial infarctions	No difference
ACCORD[14] (2008)	Reduced retinopathy, nephropathy, neuropathy	No difference on MACE	Increased mortality
ADVANCE[11] (2008)	Reduced nephropathy	No effect on MACE	No difference
VADT[12] (2009)	Reduced progression of albuminuria	No effects on major cardiovascular events	No difference

Note the lack of difference in macrovascular complications despite reduced microvascular complications, which is consistent among all studies. MACE: Major adverse cardiovascular events; DCCT: Diabetes Control and Complications Trial; T1DM: Type 1 diabetes mellitus; UKPDS: United Kingdom Prospective Diabetes Study; ACCORD: Action to Control Cardiovascular Risk in Diabetes; ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; VADT: Veterans Affairs Diabetes Trial.

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.