PURPOSE: The purpose of this study was to review the results of clinical trials 
assessing the cardiovascular effects of drugs for type 2 diabetes and the 
cardiovascular effects of newer available drugs.
METHODS: We performed a detailed search of PubMed-listed publications, reports 
from international meetings, and ongoing studies from clinical trials.gov.
FINDINGS: Currently available drugs have neutral or, in some cases, negative 
effects on cardiovascular outcomes. Modern sulfonylureas appear to be safe, 
although the biguanide metformin has a slightly better cardiovascular safety 
profile than the sulfonylureas and is the first choice for monotherapy. The 
cardiovascular tolerability of thiazolidinediones (glitazones) remains 
controversial, with particularly adverse effects in patients with cardiac 
failure. The cardiovascular effects of insulin in type 2 diabetes appear 
neutral. Newer incretin-based therapies have been closely examined in a large 
number of clinical trials, some of which are still ongoing. The dipeptidyl 
peptidase-4 inhibitor (gliptins) trials to date have all found a neutral effect. 
Of the glucagon-like peptide-1 (GLP-1) agonists, lixisenatide had a neutral 
effect, whereas liraglutide and semaglutide had a benefit on outcomes. The 
results of the sodium-glucose transporter-2 (SGLT-2) inhibitor empaglifozin 
attracted interest when it was the first to report a strong benefit on 
cardiovascular mortality. Liraglutide and semaglutide had a neutral effect on 
cardiac failure admissions, whereas empaglifozin had a benefit. In each of the 
trials, there was not a clear effect on myocardial infarction and stroke. The 
mechanism of the cardiovascular benefit is debated, and further studies with 
other GLP-1 agonists and SGLT-2 inhibitors are awaited.
IMPLICATIONS: After 2 decades of disappointment in attempting to control 
cardiovascular progression in type 2 diabetes with careful glycemic control, 
there is distinct hope that newer drugs, particularly the GLP-1 agonists and the 
SGLT-2 inhibitors, will have cardiovascular benefits independent of glycemic 
control.