4.2.0.0 Ini­tial Ther­a­py

Met­formin should be start­ed at the time type 2 di­a­betes is di­ag­nosed un­less there are con­traindi­ca­tions; for most pa­tients this will be monother­a­py in com­bi­na­tion with lifestyle modifications. Met­formin is ef­fec­tive and safe, is in­ex­pen­sive, and may re­duce risk of car­dio­vas­cu­lar events and death (40). Met­formin is avail­able in an im­me­di­ate-‍re­lease form for twicedai­ly dos­ing or as an ex­tend­ed-‍re­lease form that can be given once daily. Com­pared with sul­fony­lureas, met­formin as first-‍line ther­a­py has beneficial ef­fects on A1C, weight, and car­dio­vas­cu­lar mor­tal­i­ty (41); there is lit­tle sys­tematic data avail­able for other oral agents as ini­tial ther­a­py of type 2 di­a­betes. The prin­ci­pal side ef­fects of met­formin are gas­troin­testi­nal in­tol­er­ance due to bloat­ing, ab­dom­i­nal dis­com­fort, and di­ar­rhea. The drug is cleared by renal filtra­tion, and very high cir­cu­lat­ing lev­els (e.g., as a re­sult of over­dose or acute renal fail­ure) have been as­so­ci­at­ed with lac­tic aci­do­sis. How­ev­er, the oc­cur­rence of this com­pli­ca­tion is now known to be very rare, and met­formin may be safe­ly used in pa­tients with re­duced es­ti­mat­ed glomeru­lar filtra­tion rates (eGFR); the FDA has re­vised the label for met­formin to reflect its safe­ty in pa­tients with eGFR ≥30 mL/‍min/‍1.73 m2 (42). A re­cent ran­dom­ized trial confirmed pre­vi­ous ob­ser­va­tions that met­formin use is as­so­ci­at­ed with vi­ta­min B12 deficien­cy and wors­en­ing of symp­toms of neu­ropa­thy (43). This is com­pat­i­ble with a re­cent re­port from the Di­a­betes Pre­ven­tion Pro­gram Out­comes Study (DPPOS) sug­gest­ing pe­ri­od­ic test­ing of vi­ta­min B12 (44).

In pa­tients with con­traindi­ca­tions or in­tol­er­ance of met­formin, ini­tial ther­a­py should be based on pa­tient fac­tors; con­sid­er a drug from an­oth­er class de­pict­ed in Fig. 9.1. When A1C is ≥1.5% (12.5 mmol/‍mol) above glycemic tar­get (see Sec­tion 6 “Glycemic Tar­gets” for more in­for­ma­tion on se­lect­ing ap­pro­pri­ate tar­gets), many pa­tients will re­quire dual com­bi­na­tion ther­a­py to achieve their tar­get A1C level (45). In­sulin has the ad­van­tage of being ef­fec­tive where other agents are not and should be con­sid­ered as part of any com­bi­na­tion reg­i­men when hy­per­glycemia is se­vere, es­pe­cial­ly if catabol­ic fea­tures (weight loss, hy­per­triglyc­eridemia, ke­to­sis) are pre­sent. Con­sid­er ini­ti­at­ing in­sulin ther­a­py when blood glu­cose is ≥300 mg/dL (16.7 mmol/‍L) or A1C is ≥10% (86 mmol/‍mol) or if the pa­tient has symp­toms of hy­per­glycemia (i.e., polyuria or poly­dip­sia), even at di­ag­no­sis or early in the course of treat­ment (Fig. 9.2). As glu­cose tox­i­c­i­ty re­solves, sim­pli­fy­ing the reg­i­men and/‍or chang­ing to oral agents is often pos­si­ble.

Fig­ure 9.2 In­ten­sifying to in­jectable ther­a­pies