4.2.0.0 A1C and Mi­crovas­cu­lar Com­pli­ca­tions

Hy­per­glycemia defines di­a­betes, and glycemic con­trol is fun­da­men­tal to di­a­betes man­age­ment. The Di­a­betes Con­trol and Com­pli­ca­tions Trial (DCCT) (16), a prospec­tive ran­dom­ized con­trolled trial of in­ten­sive (mean A1C about 7% [53 mmol/‍mol]) ver­sus stan­dard (mean A1C about 9% [75 mmol/‍mol]) glycemic con­trol in pa­tients with type 1 di­a­betes, showed defini­tive­ly that bet­ter glycemic con­trol is as­so­ci­at­ed with 50–76% re­duc­tions in rates of de­vel­op­ment and pro­gres­sion of mi­crovas­cu­lar (retinopa­thy, neu­ropa­thy, and di­a­bet­ic kid­ney dis­ease) com­pli­ca­tions. Fol­low-‍up of the DCCT co­horts in the Epi­demi­ol­o­gy of Di­a­betes In­ter­ven­tions and Com­pli­ca­tions (EDIC) study (17,18) demon­strat­ed per­sis­tence of these mi­crovas­cu­lar benefits over two decades de­spite the fact that the glycemic sep­a­ra­tion be­tween the treat­ment groups di­min­ished and dis­ap­peared dur­ing fol­low-‍up.

The Ku­mamo­to Study (19) and UK Prospec­tive Di­a­betes Study (UKPDS) (20,21) confirmed that in­ten­sive glycemic con­trol significant­ly de­creased rates of mi­crovas­cu­lar com­pli­ca­tions in pa­tients with short-‍du­ra­tion type 2 di­a­betes. Long-‍term fol­low-‍up of the UKPDS co­horts showed endur­ing ef­fects of early glycemic con­trol on most mi­crovas­cu­lar com­pli­ca­tions (22).

There­fore, achiev­ing A1C tar­gets of <7% (53 mmol/‍mol) has been shown to re­duce mi­crovas­cu­lar com­pli­ca­tions of type 1 and type 2 di­a­betes when in­sti­tut­ed early in the course of dis­ease. Epi­demi­o­log­ic anal­y­ses of the DCCT (16) and UKPDS (23) demon­strate a curvi­lin­ear re­la­tion­ship be­tween A1C and mi­crovas­cu­lar com­pli­ca­tions. Such anal­y­ses sug­gest that, on a pop­u­la­tion level, the great­est num­ber of com­pli­ca­tions will be avert­ed by tak­ing pa­tients from very poor con­trol to fair/‍good con­trol. These anal­y­ses also sug­gest that fur­ther low­er­ing of A1C from 7% to 6% [53 mmol/‍mol to 42 mmol/‍mol] is as­so­ci­at­ed with fur­ther re­duc­tion in the risk of mi­crovas­cu­lar com­pli­ca­tions, al­though the ab­so­lute risk re­duc­tions be­come much small­er. Given the sub­stan­tial­ly in­creased risk of hy­po­glycemia in type 1 di­a­betes tri­als and with polyphar­ma­cy in type 2 di­a­betes, the risks of lower glycemic tar­gets may out­weigh the po­ten­tial benefits on mi­crovas­cu­lar com­pli­ca­tions.

Three land­mark tri­als (Ac­tion to Con­trol Car­dio­vas­cu­lar Risk in Di­a­betes [AC­CORD], Ac­tion in Di­a­betes and Vas­cu­lar Dis­ease: Preter­ax and Di­ami­cron MR Con­trolled Eval­u­a­tion [AD­VANCE], and Vet­er­ans Af­fairs Di­a­betes Trial [VADT]) were con­duct­ed to test the ef­fects of near nor­mal­iza­tion of blood glu­cose on car­dio­vas­cu­lar out­comes in in­di­vid­u­als with long-‍stand­ing type 2 di­a­betes and ei­ther known car­dio­vas­cu­lar dis­ease (CVD) or high car­dio­vas­cu­lar risk. These tri­als showed that lower A1C lev­els were as­so­ci­at­ed with re­duced onset or pro­gres­sion of some mi­crovas­cu­lar com­pli­ca­tions (24-26).

The con­cern­ing mor­tal­i­ty find­ings in the AC­CORD trial (27), dis­cussed below, and the rel­a­tive­ly in­tense ef­forts re­quired to achieve near eu­g­lycemia should also be con­sid­ered when set­ting glycemic tar­gets for in­di­vid­u­als with long-‍stand­ing di­a­betes such as those stud­ied in AC­CORD, AD­VANCE, and VADT.

Find­ings from these stud­ies sug­gest cau­tion is need­ed in treat­ing di­a­betes ag­gres­sive­ly to near-‍nor­mal A1C goals in peo­ple with long-‍stand­ing type 2 di­a­betes with or at significant risk of CVD. How­ev­er, on the basis of physi­cian judg­ment and pa­tient pref­er­ences, se­lect pa­tients, es­pe­cial­ly those with lit­tle co­mor­bidity and long life ex­pectan­cy, may benefit from adopt­ing more in­ten­sive glycemic tar­gets (e.g., A1C tar­get <6.5% [48 mmol/‍mol]) if they can achieve it safe­ly with­out hy­po­glycemia or significant ther­a­peu­tic bur­den.