4.4.0.0 Car­dio­vas­cu­lar Out­comes Tri­als

There are now mul­ti­ple large ran­dom­ized con­trolled tri­als re­porting sta­tis­ti­cal­ly significant re­duc­tions in car­dio­vas­cu­lar events in pa­tients with type 2 di­a­betes treat­ed with an SGLT2 in­hibitor (em­pagliflozin, canagliflozin) or GLP-1 re­cep­tor ag­o­nist (li­raglu­tide, semaglu­tide). In peo­ple with di­a­betes with es­tab­lished ASCVD, em­pagliflozin de­creased a com­pos­ite three-‍point major car­dio­vas­cu­lar event (MACE) out­come and mor­tal­i­ty com­pared with place­bo (54). Sim­i­lar­ly, canagliflozin re­duced the oc­cur­rence of MACE in a group of sub­jects with, or at high risk for, ASCVD (55). In both of these tri­als, SGLT2 in­hibitors re­duced hos­pi­tal­iza­tion for HF (54,55); this was a sec­ondary out­come of these stud­ies and will re­quire confirma­tion in more defined pop­u­la­tions. In peo­ple with type 2 di­a­betes with ASCVD or in­creased risk for ASCVD, the ad­di­tion of li­raglu­tide de­creased MACE and mor­tal­i­ty (56), and the close­ly re­lat­ed GLP-1 re­cep­tor ag­o­nist semaglu­tide also had fa­vor­able ef­fects on car­dio­vas­cu­lar end points in high-‍risk sub­jects (57). In these car­dio­vas­cu­lar out­comes tri­als, em­pagliflozin, canagliflozin, li­raglu­tide, and semaglu­tide all had beneficial ef­fects on com­pos­ite in­dices of CKD (54-57). See AN­TI­HY­PER­GLYCEMIC THER­A­PIES AND CAR­DIO­VAS­CU­LAR OUT­COMES in Sec­tion 10 “Car­dio­vas­cu­lar Dis­ease and Risk Man­age­ment” and Table 10.4 for a de­tailed de­scrip­tion of these car­dio­vas­cu­lar out­comes tri­als, as well as a dis­cus­sion of how HF may im­pact treat­ment choic­es. See Sec­tion 11 “Mi­crovas­cu­lar Com­pli­ca­tions and Foot Care” for a de­tailed dis­cus­sion on how CKD may im­pact treat­ment choic­es. Ad­di­tion­al large ran­dom­ized tri­als of other agents in these class­es are on­go­ing.

The sub­jects en­rolled in the car­dio­vas­cu­lar out­comes tri­als using em­pagliflozin, canagliflozin, li­raglu­tide, and semaglu­tide had A1C ≥7%, and more than 70% were tak­ing met­formin at base­line. More­over, the benefit of treat­ment was less ev­i­dent in sub­jects with lower risk for ASCVD. Thus, ex­ten­sion of these re­sults to prac­tice is most ap­pro­pri­ate for peo­ple with type 2 di­a­betes and es­tab­lished ASCVD who re­quire ad­di­tional glucose-‍low­er­ing treat­ment be­yond met­formin and lifestyle man­age­ment. For these pa­tients, in­cor­po­rat­ing one of the SGLT2 in­hibitors or GLP-1 re­cep­tor ag­o­nists that have been demon­strat­ed to re­duce car­dio­vas­cu­lar events is rec­om­mend­ed (Table 9.1).