4.3.2.0 Car­dio­vas­cu­lar Dis­ease and Type 2 Di­a­betes

In type 2 di­a­betes, there is ev­i­dence that more in­ten­sive treat­ment of glycemia in newly di­ag­nosed pa­tients may re­duce long-‍term CVD rates. Dur­ing the UKPDS, there was a 16% re­duc­tion in CVD events (com­bined fatal or non­fa­tal MI and sud­den death) in the in­ten­sive glycemic con­trol arm that did not reach sta­tis­ti­cal significance (P = 0.052), and there was no sug­gestion of benefit on other CVD out­comes (e.g., stroke). How­ev­er, after 10 years of ob­ser­va­tion­al fol­low-‍up, those orig­i­nal­ly ran­dom­ized to in­ten­sive glycemic con­trol had significant long-‍term re­duc­tions in MI (15% with sul­fony­lurea or in­sulin as ini­tial pharmacother­a­py, 33% with met­formin as ini­tial pharmacother­a­py) and in all-‍cause mor­tal­i­ty (13% and 27%, re­spec­tive­ly) (22).

AC­CORD, AD­VANCE, and VADT sug­gested no significant re­duc­tion in CVD out­comes with in­ten­sive glycemic con­trol in par­tic­i­pants fol­lowed for short­er du­ra­tions (3.5–5.6 years) and who had more ad­vanced type 2 di­a­betes than UKPDS par­tic­i­pants. All three tri­als were con­duct­ed in rel­a­tive­ly older par­tic­i­pants with longer known du­ra­tion of di­a­betes (mean du­ra­tion 8–11 years) and ei­ther CVD or mul­ti­ple car­dio­vas­cu­lar risk fac­tors. The tar­get A1C among in­ten­sive-‍con­trol sub­jects was <6% (42 mmol/‍mol) in AC­CORD, <6.5% (48 mmol/‍mol) in AD­VANCE, and a 1.5% re­duc­tion in A1C com­pared with con­trol sub­jects in VADT, with achieved A1C of 6.4% vs. 7.5% (46 mmol/‍mol vs. 58 mmol/‍mol) in AC­CORD, 6.5% vs. 7.3% (48 mmol/‍mol vs. 56 mmol/‍mol) in AD­VANCE, and 6.9% vs. 8.4% (52 mmol/‍mol vs. 68 mmol/‍mol) in VADT. De­tails of these stud­ies are re­viewed ex­ten­sively in “In­ten­sive Glycemic Con­trol and the Pre­ven­tion of Car­dio­vas­cu­lar Events: Im­pli­ca­tions of the AC­CORD, AD­VANCE, and VA Di­a­betes Tri­als” (31).

The glycemic con­trol com­par­i­son in AC­CORD was halt­ed early due to an in­creased mor­tal­i­ty rate in the in­ten­sive com­pared with the stan­dard treat­ment arm (1.41% vs. 1.14% per year; haz­ard ratio 1.22 [95% CI 1.01–1.46]), with a sim­i­lar in­crease in car­dio­vas­cu­lar deaths. Anal­y­sis of the AC­CORD data did not iden­ti­fy a clear ex­pla­na­tion for the ex­cess mor­tal­i­ty in the in­ten­sive treat­ment arm (27).

Longer-‍term fol­low-‍up has shown no ev­i­dence of car­dio­vas­cu­lar benefit or harm in the AD­VANCE trial (32). The end-‍stage renal dis­ease rate was lower in the in­ten­sive treat­ment group over fol­low-‍up. How­ev­er, 10-year fol­low-‍up of the VADT co­hort (33) showed a re­duc­tion in the risk of car­dio­vas­cu­lar events (52.7 [con­trol group] vs. 44.1 [in­ter­ven­tion group] events per 1,000 per­son-‍years) with no benefit in car­dio­vas­cu­lar or over­all mor­tal­i­ty. Het­ero­gene­ity of mor­tal­i­ty ef­fects across stud­ies was noted, which may reflect dif­fer­ences in glycemic tar­gets, ther­a­peu­tic ap­proach­es, and pop­u­la­tion char­ac­ter­is­tics (34).

Mor­tal­i­ty find­ings in AC­CORD (27) and sub­group anal­y­ses of VADT (35) sug­gest that the po­ten­tial risks of in­ten­sive glycemic con­trol may out­weigh its benefits in high­er-‍risk pa­tients. In all three tri­als, se­vere hy­po­glycemia was significant­ly more like­ly in par­tic­i­pants who were ran­dom­ly as­signed to the in­ten­sive glycemic con­trol arm. Those pa­tients with long du­ra­tion of di­a­betes, a known his­to­ry of hy­po­glycemia, ad­vanced atheroscle­ro­sis, or ad­vanced age/‍frailty may benefit from less ag­gres­sive tar­gets (36,37).

As dis­cussed fur­ther below, se­vere hy­po­glycemia is a po­tent mark­er of high ab­so­lute risk of car­dio­vas­cu­lar events and mor­tal­i­ty (38). Providers should be vig­i­lant in pre­vent­ing hy­po­glycemia and should not ag­gres­sive­ly at­tempt to achieve near-‍nor­mal A1C lev­els in pa­tients in whom such tar­gets can­not be safe­ly and rea­son­ably achieved.

As dis­cussed in Sec­tion 9 “Phar­ma­co­logic Ap­proach­es to Glycemic Treat­ment,” ad­di­tion of specific sodi­um–glu­cose co­trans­porter 2 in­hibitors (SGLT2i) or glucagon-‍like pep­tide 1 re­cep­tor ag­o­nists (GLP-1 RA) to im­prove car­dio­vas­cu­lar out­comes in pa­tients with es­tab­lished CVD is in­di­cat­ed with con­sid­er­a­tion of glycemic goals. If the pa­tient is not at A1C tar­get, con­tin­ue met­formin un­less contrain­di­cat­ed and add SGLT2i or GLP-1 RA with proven car­dio­vas­cu­lar benefit. If the pa­tient is meet­ing A1C tar­get, con­sider one of three strate­gies (39):

  1. If al­ready on dual ther­a­py or mul­ti­ple glu­cose-‍low­er­ing ther­a­pies and not on an SGLT2i or GLP-1 RA, con­sid­er switch­ing to one of these agents with proven car­dio­vas­cu­lar benefit.
  2. Recon­sid­er/lower in­di­vid­u­alized A1C tar­get and in­tro­duce SGLT2i or GLP-1 RA.
  3. Reas­sess A1C at 3-‍month in­ter­vals and add SGLT2i or GLP-1 RA if A1C goes above tar­get.