2.2.0.0 In­sulin Ther­a­py

Be­cause the hall­mark of type 1 di­a­betes is ab­sent or near-‍ab­sent β-cell func­tion, in­sulin treat­ment is es­sen­tial for in­di­vid­u­als with type 1 di­a­betes. Insufficient pro­vi­sion of in­sulin caus­es not only hy­per­glycemia but also sys­tematic metabol­ic dis­tur­bances like hy­per­triglyc­eridemia and ke­toaci­do­sis, as well as tis­sue catabolism. Over the past three decades, ev­i­dence has ac­cu­mu­lat­ed sup­port­ing mul­ti­ple daily in­jec­tions of in­sulin or con­tin­u­ous sub­cu­ta­neous ad­min­is­tra­tion through an in­sulin pump as pro­vid­ing the best com­bi­na­tion of ef­fec­tive­ness and safe­ty for peo­ple with type 1 di­a­betes.

Gen­er­al­ly, in­sulin re­quire­ments can be es­ti­mat­ed based on weight, with typ­i­cal doses rang­ing from 0.4 to 1.0 units/‍kg/‍day. High­er amounts are re­quired dur­ing pu­ber­ty, preg­nan­cy, and med­i­cal ill­ness. The Amer­i­can Di­a­betes As­so­ci­a­tion/JDRF Type 1 Di­a­betes Source­book notes 0.5 units/‍kg/‍day as a typ­i­cal start­ing dose in pa­tients with type 1 di­a­betes who are metabol­ically sta­ble, with half ad­min­is­tered as pran­di­al in­sulin given to con­trol blood glu­cose after meals and the other half as basal in­sulin to con­trol glycemia in the pe­ri­ods be­tween meal ab­sorp­tion (1); this guide­line pro­vides de­tailed in­for­ma­tion on in­ten­sification of ther­a­py to meet in­di­vid­u­al­ized needs. In ad­di­tion, the Amer­i­can Di­a­betes As­so­ci­a­tion po­si­tion state­ment “Type 1 Di­a­betes Man­age­ment Through the Life Span” pro­vides a thor­ough overview of type 1 di­a­betes treat­ment (2).

Phys­i­o­log­ic in­sulin se­cre­tion varies with glycemia, meal size, and tis­sue de­mands for glu­cose. To ap­proach this vari­abil­i­ty in peo­ple using in­sulin treat­ment, strate­gies have evolved to ad­just pran­di­al doses based on pre­dict­ed needs. Thus, ed­u­ca­tion of pa­tients on how to ad­just pran­di­al in­sulin to ac­count for car­bo­hy­drate in­take, pre­meal glu­cose lev­els, and an­tic­i­pat­ed ac­tiv­i­ty can be ef­fec­tive and should be con­sid­ered. Newly avail­able in­for­ma­tion sug­gests that in­di­vid­u­als in whom car­bo­hy­drate count­ing is ef­fec­tive can in­cor­po­rate es­ti­mates of meal fat and pro­tein con­tent into their pran­di­al dos­ing for added benefit (3-5).

Most stud­ies com­par­ing mul­ti­ple daily in­jec­tions with con­tin­u­ous sub­cu­ta­neous in­sulin in­fu­sion (CSII) have been rel­a­tive­ly small and of short du­ra­tion. How­ev­er, a re­cent sys­tematic re­view and meta-‍anal­y­sis con­clud­ed that pump ther­a­py has mod­est ad­van­tages for low­er­ing A1C (–0.30% [95% CI –0.58 to –0.02]) and for re­duc­ing se­vere hy­po­glycemia rates in chil­dren and adults (6). There is no con­sen­sus to guide choos­ing which form of in­sulin ad­min­is­tra­tion is best for a given pa­tient, and re­search to guide this de­ci­sion mak­ing is need­ed (7). The ar­rival of con­tin­u­ous glu­cose mon­i­tors to clin­i­cal prac­tice has proven beneficial in specific cir­cum­stances. Re­duc­tion of noc­tur­nal hy­po­glycemia in peo­ple with type 1 di­a­betes using in­sulin pumps with glu­cose sen­sors is im­proved by au­to­mat­ic sus­pen­sion of in­sulin de­liv­ery at a pre­set glu­cose level (7-9). The U.S. Food and Drug Ad­min­is­tra­tion (FDA) has also ap­proved the first hy­brid closed-‍loop pump sys­tem. The safe­ty and efficacy of hy­brid closed-‍loop sys­tems has been sup­port­ed in the lit­er­a­ture in ado­les­cents and adults with type 1 di­a­betes (10,11). In­ten­sive di­a­betes man­age­ment using CSII and con­tin­u­ous glu­cose mon­i­tor­ing should be con­sid­ered in se­lect­ed pa­tients. See Sec­tion 7 “Di­a­betes Tech­nol­o­gy” for a full dis­cus­sion of in­sulin de­liv­ery de­vices.

The Di­a­betes Con­trol and Com­pli­ca­tions Trial (DCCT) demon­strat­ed that in­ten­sive ther­a­py with mul­ti­ple daily in­jec­tions or CSII re­duced A1C and was as­so­ci­at­ed with im­proved long-‍term out­comes (12-14). The study was car­ried out with short-‍act­ing and in­ter­me­di­ate-‍act­ing human in­sulins. De­spite bet­ter mi­crovas­cu­lar, macrovas­cu­lar, and all-‍cause mor­tal­i­ty out­comes, in­ten­sive ther­a­py was as­so­ci­at­ed with a high­er rate of se­vere hy­po­glycemia (61 episodes per 100 pa­tient-‍years of ther­a­py). Since the DCCT, rapid-‍act­ing and long-‍act­ing in­sulin ana­logs have been de­vel­oped. These ana­logs are as­so­ci­at­ed with less hy­po­glycemia, less weight gain, and lower A1C than human in­sulins in peo­ple with type 1 di­a­betes (15-17). Longer-‍act­ing basal ana­logs (U-300 glargine or degludec) may con­vey a lower hy­po­glycemia risk com­pared with U-100 glargine in pa­tients with type 1 di­a­betes (18,19). Rapid-‍act­ing in­haled in­sulin to be used be­fore meals is now avail­able and may re­duce rates of hy­po­glycemia in pa­tients with type 1 di­a­betes (20).

Postpran­di­al glu­cose ex­cur­sions may be bet­ter con­trolled by ad­justing the tim­ing of pran­di­al in­sulin dose ad­min­is­tra­tion. The op­ti­mal time to ad­min­is­ter pran­di­al in­sulin varies, based on the type of in­sulin used (reg­u­lar, rapid-‍act­ing ana­log, in­haled, etc.), mea­sured blood glu­cose level, tim­ing of meals, and car­bo­hy­drate con­sump­tion. Rec­om­men­da­tions for pran­di­al in­sulin dose ad­min­is­tra­tion should there­fore be in­di­vid­u­al­ized.

In­sulin In­jec­tion Tech­nique

En­sur­ing that pa­tients and/‍or care­givers un­der­stand cor­rect in­sulin in­jec­tion tech­nique is im­por­tant to op­ti­mize glu­cose con­trol and in­sulin use safe­ty. Thus, it is im­por­tant that in­sulin be de­liv­ered into the prop­er tis­sue in the right way. Rec­om­men­da­tions have been pub­lished else­where out­lin­ing best prac­tices for in­sulin in­jec­tion (21). Prop­er in­sulin in­jec­tion tech­nique in­cludes in­ject­ing into ap­pro­pri­ate body areas, in­jec­tion site ro­ta­tion, ap­pro­pri­ate care of in­jec­tion sites to avoid in­fec­tion or other com­pli­ca­tions, and avoid­ance of in­tra­mus­cu­lar (IM) in­sulin de­liv­ery.

Exogenous-de­liv­ered in­sulin should be in­ject­ed into sub­cu­ta­neous tis­sue, not in­tra­mus­cu­larly. Rec­om­mend­ed sites for in­sulin in­jec­tion in­clude the ab­domen, thigh, but­tock, and upper arm (21). Be­cause in­sulin ab­sorp­tion from IM sites dif­fers ac­cord­ing to the ac­tiv­i­ty of the mus­cle, in­ad­ver­tent IM in­jec­tion can lead to un­pre­dictable in­sulin ab­sorp­tion and vari­able ef­fects on glu­cose, with IM in­jec­tion being as­so­ci­at­ed with fre­quent and un­ex­plained hy­po­glycemia in sev­er­al re­ports (21-23). Risk for IM in­sulin de­liv­ery is in­creased in younger and lean pa­tients when in­ject­ing into the limbs rather than trun­cal sites (ab­domen and but­tocks) and when using longer nee­dles (24). Re­cent ev­i­dence sup­ports the use of short nee­dles (e.g., 4-mm pen nee­dles) as ef­fec­tive and well tol­er­at­ed when com­pared to longer nee­dles (25,26), in­clud­ing a study per­formed in obese adults (27). In­jec­tion site ro­ta­tion is ad­di­tionally nec­es­sary to avoid lipo­hy­per­tro­phy and lipoa­t­ro­phy (21). Lipo­hy­per­tro­phy can con­tribute to er­rat­ic in­sulin ab­sorp­tion, in­creased glycemic vari­abil­i­ty, and un­ex­plained hy­po­glycemic episodes (28). Pa­tients and/‍or care­givers should re­ceive ed­u­ca­tion about prop­er in­jec­tion site ro­ta­tion and to rec­og­nize and avoid areas of lipo­hy­per­tro­phy (21). As noted in Table 4.1, ex­am­i­na­tion of in­sulin in­jec­tion sites for the pres­ence of lipo­hy­per­tro­phy, as well as as­sess­ment of in­jec­tion de­vice use and in­jec­tion tech­nique, are key com­po­nents of a com­pre­hen­sive di­a­betes med­i­cal eval­u­a­tion and treat­ment plan. As ref­er­enced above, there are now nu­mer­ous ev­i­dence-‍based in­sulin de­liv­ery rec­om­men­da­tions that have been pub­lished. Prop­er in­sulin in­jec­tion tech­nique may lead to more ef­fec­tive use of this ther­a­py and, as such, holds the po­ten­tial for im­proved clin­i­cal out­comes.