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Table 1 Classes of glucose lowering agents: main findings of CVOTs and other important trials

From: From glucose lowering agents to disease/diabetes modifying drugs: a “SIMPLE” approach for the treatment of type 2 diabetes

Group of drugs Specific brands Dosing Comments CVOTs / CROTs
SGLT2 inhibitors Canagliflozin 100, 300 mg QD Proven reduction in 3-point MACE, hHF, all-cause mortality and ”hard” renal outcomes in population of patients with/or risk factors for/ or previous ASCVD, as well as in population of patients with proteinuric diabetic nephropathy. Increased risk for fractures and amputations in one outcome trial (CANVAS) but not in the other (CREDENCE) CANVAS Program [13, 87]
CREDENCE [69]
Dapagliflozin 5, 10 mg QD Proven reduction in hHF/CVD and ”hard” renal outcomes in population of patients with risk factors for/or previous ASCVD. Proven reduction in CV death and hHF in populations of patients with HFrEF with or without diabetes. Proven reduction in a composite of clinically important kidney outcomes and renal or CV death, in patients with CKD with or without diabetes DECLARE-TIMI 58 [16, 88]
DAPA-HF [89]
DAPA-CKD [70]
Empagliflozin 10, 25 mg QD Proven reduction in 3-point MACE, CV death, hHF, all-cause mortality and ”hard” renal outcomes in populations of patients with previous ASCVD. Proven reduction in CV death and hHF in populations of patients with HFrEF with or without diabetes EMPA-REG
OUTCOME [10, 56]
EMPEROR-Reduced [90]
Ertugliflozin 5, 15 mg QD CVOT in population of patients with ASCVD reported CV safety both regarding 3-point MACE and CVD/hHF. Lower rate of hHF, and a trend towards improved renal outcome VERTIS-CV [48]
SGLT2 & SGLT1 inhibitor Sotagliflozin 200, 400 mg QD Reduction in CV death, hHF or urgent visit due to HF in patients with type 2 diabetes and chronic kidney disease (SCORED), or after a recent episode of decompensated HF (SOLOIST-WHF). The studies were terminated early due to loss of funding. Higher incidence of diarrhea was observed, as well as genital mycotic infections, volume depletion, and diabetic ketoacidosis (SCORED) or hypoglycemic episodes (SOLOIST-WHF) SCORED [91]
SOLOIST-WHF [92]
GLP-1 receptor agonist Albiglutide 30, 50 mg QW SC Proven reduction in 3-point MACE and CV death in population of patients with risk factors for/or previous ASCVD. Currently not marketed HARMONY Outcomes [15]
Dulaglutide 0·75, 1·5 mg QW SC Proven reduction in 3-point MACE in population of patients with risk factors for/or previous ASCVD. Improvement in secondary renal composite outcome REWIND [17, 93]
Exenatide XR 2 mg QW SC Proven CV safety in population of patients with risk factors for/ or previous ASCVD EXSCEL [14]
Liraglutide 1·2–1·8 QD SC Proven reduction in 3-point MACE and CV death in population of patients with risk factors (minority) or with previous (majority) ASCVD LEADER [11]
Lixisenatide 10, 20 mcg QD SC Proven CV safety in population of patients with recent acute coronary syndrome (ACS) ELIXA [9]
Semaglutide 0·5, 1 mg QW SC A pre-approval trial demonstrated reduction in 3-point MACE and CVA, but showed an increased risk for worsening of retinopathy in population with mostly ASCVD or CKD but some patients with only CV risk factors. More effective than other GLP-1 RAs in weight reduction and glucose control SUSTAIN-6 [12]
Semaglutide (Oral) 7, 14 mg QD PO In a smaller pre-approval trial, proven CV safety in population of patients with risk factors for/or previous ASCVD. Demonstrated reduction in CV death and all-cause mortality. A larger CVOT is ongoing PIONEER-6 [54]
SOUL [94]
DPP4- inhibitors Alogliptin 12·5, 25 mg QD Proven CV safety in population of patients with recent ACS EXAMINE [83]
Linagliptin 5 mg QD Proven CV safety in population of patients with risk factors for/or previous ASCVD. No further CV benefit over sulfonylurea (SU) CARMELINA [55]
CAROLINA [63]
Saxagliptin 2·5, 5 mg QD Proven CV safety in population of patients with risk factors for/or previous ASCVD. Increased risk for hHF SAVOR-TIMI 53 [84]
Sitagliptin 25,50,100 mg QD Proven CV safety in population of patients with previous ASCVD TECOS [85]
Vildagliptin 50 mg BID CV safety not tested  
TZDs Pioglitazone 15, 30, 45 mg QD Proven CV safety and possibly efficacy, reduced 3-point MACE in patients with insulin resistance but without diabetes after previous cerebrovascular event. Increased risk of HF, weight gain, fractures in post-menopausal women PROactive [95]
IRIS [86]
Insulin Degludec   Proven CV safety in population of patients with risk factors for/or previous ASCVD DEVOTE [96]
Glargine   Proven CV safety in population of patients with risk factors for/or previous ASCVD, with diabetes or pre-diabetes ORIGIN [97]
Biguanides Metformin   Proven CV efficacy in small population of patients with relatively new onset type 2 diabetes. In a subgroup of patients treated with sulfonylurea, added metformin was associated with increased diabetes related death UKPDS [41, 42]
  1. ASCVD atherosclerotic cardiovascular disease, CKD chronic kidney disease, CROT cardiorenal outcome trial, CV cardiovascular, CVA cerebrovascular accident, CVD cardiovascular disease, CVOT cardiovascular outcome trial, DPP4i dipeptidyl peptidase 4 inhibitors, GLP-1 glucagon-like peptide-1, HFrEF heart failure with reduced ejection fraction, hHF hospitalization for heart failure, MACE major adverse cardiovascular events, SGLT1 sodium glucose co-transporter type 1, SGLT2 sodium glucose co-transporter type 2, TZDs Thiazolidinediones