4.3.0.0 Com­bi­na­tion Ther­a­py

Al­though there are nu­mer­ous tri­als com­par­ing dual ther­a­py with met­formin alone, few di­rect­ly com­pare drugs as add-‍on ther­a­py. A com­par­a­tive ef­fec­tive­ness meta-‍anal­y­sis sug­gests that each new class of nonin­sulin agents added to ini­tial ther­a­py gen­er­ally low­ers A1C ap­prox­i­mate­ly 0.7–1.0% (46). If the A1C tar­get is not achieved after ap­prox­i­mate­ly 3 months and the pa­tient does not have ASCVD or CKD, con­sid­er a com­bi­na­tion of met­formin and any one of the pre­ferred six treat­ment op­tions: sul­fony­lurea, thi­a­zo­lidine­dione, dipep­tidyl pep­ti­dase 4 (DPP-4) in­hibitor, SGLT2 in­hibitor, GLP-1 re­cep­tor ag­o­nist, or basal in­sulin; the choice of which agent to add is based on drug-‍specific ef­fects and pa­tient fac­tors (Fig. 9.1 and Table 9.1). For pa­tients in whom ASCVD, HF, or CKD pre­dom­i­nates, the best choice for a sec­ond agent is a GLP-1 re­cep­tor ag­o­nist or SGLT2 in­hibitor with demon­strat­ed car­dio­vas­cu­lar risk re­duc­tion, after con­sid­er­a­tion of drug-‍specific and pa­tient fac­tors (Table 9.1). For pa­tients with­out es­tab­lished ASCVD or CKD, the choice of a sec­ond agent to add to met­formin is not yet guid­ed by em­pir­ic ev­i­dence. Rather, drug choice is based on avoid­ance of side ef­fects, par­tic­u­lar­ly hy­po­glycemia and weight gain, cost, and pa­tient pref­er­ences (47). Sim­i­lar con­sid­er­a­tions are ap­plied in pa­tients who re­quire a third agent to achieve glycemic goals; there is also very lit­tle trial-‍based ev­i­dence to guide this choice. In all cases, treat­ment reg­i­mens need to be con­tin­u­ously re­viewed for efficacy, side ef­fects, and pa­tient bur­den (Table 9.1). In some in­stances, pa­tients will re­quire med­i­ca­tion re­duc­tion or dis­con­tin­u­a­tion. Com­mon rea­sons for this in­clude inef­fec­tive­ness, in­tol­er­a­ble side ef­fects, ex­pense, or a change in glycemic goals (e.g., in re­sponse to de­vel­op­ment of co­mor­bidi­ties or changes in treat­ment goals). See Sec­tion 12 "Older Adults” for a full dis­cus­sion of treat­ment con­sid­er­a­tions in older adults.

Even though most pa­tients pre­fer oral med­i­ca­tions to drugs that need to be in­ject­ed, the even­tu­al need for the greater po­ten­cy of in­jectable med­i­ca­tions is com­mon, par­tic­u­lar­ly in peo­ple with a longer du­ra­tion of di­a­betes. The ad­di­tion of basal in­sulin, ei­ther human NPH or one of the long-‍act­ing in­sulin ana­logs, to oral agent reg­i­mens is a well-‍es­tab­lished ap­proach that is ef­fec­tive for many pa­tients. In ad­di­tion, re­cent ev­i­dence sup­ports the util­i­ty of GLP-1 re­cep­tor ag­o­nists in pa­tients not reach­ing glycemic tar­gets with oral agent reg­i­mens. In tri­als com­par­ing the ad­di­tion of GLP-1 re­cep­tor ag­o­nists or in­sulin in pa­tients need­ing fur­ther glu­cose low­er­ing, the efficacy of the two treat­ments was sim­i­lar (48-50). How­ev­er, GLP-1 re­cep­tor ag­o­nists had a lower risk of hy­po­glycemia and beneficial ef­fects on body weight com­pared with in­sulin, al­beit with greater gas­troin­testi­nal side ef­fects. Thus, trial re­sults sup­port a GLP-1 re­cep­tor ag­o­nist as the pre­ferred op­tion for pa­tients re­quir­ing the po­ten­cy of an in­jectable ther­a­py for glu­cose con­trol (Fig. 9.2). How­ev­er, high costs and tol­er­a­bil­i­ty is­sues are im­por­tant bar­ri­ers to the use of GLP-1 re­cep­tor ag­o­nists.

Cost-‍ef­fec­tive­ness mod­els of the newer agents based on clin­i­cal util­i­ty and glycemic ef­fect have been re­port­ed (51). Table 9.2 pro­vides cost in­for­ma­tion for cur­rently ap­proved nonin­sulin ther­a­pies. Of note, prices list­ed are av­er­age whole­sale prices (AWP) (52) and Na­tion­al Av­er­age Drug Ac­qui­si­tion Costs (NADAC) (53) and do not ac­count for dis­counts, re­bates, or other price ad­justments often in­volved in pre­scrip­tion sales that af­fect the ac­tu­al cost in­curred by the pa­tient. While there are al­ter­na­tive means to es­ti­mate med­i­ca­tion prices, AWP and NADAC were uti­lized to pro­vide two sep­a­rate mea­sures to allow for a com­par­i­son of drug prices with the pri­ma­ry goal of high­light­ing the im­por­tance of cost con­sid­er­a­tions when pre­scrib­ing an­ti­hy­per­glycemic treat­ments.

Table 9.2—Me­di­an month­ly cost of max­i­mum ap­proved daily dose of nonin­sulin glu­cose-‍low­er­ing agents in the U.S.

Table 9.3—Me­di­an cost of in­sulin prod­ucts in the U.S. cal­cu­lated as AWP (44) and NADAC (45) per 1,000 units of specified dosage form/prod­uct