Hy­po­glycemia is the major lim­it­ing fac­tor in the glycemic man­age­ment of type 1 and type 2 di­a­betes. Rec­om­men­da­tions re­gard­ing the clas­sification of hy­po­glycemia are out­lined in Table 6.3 (44). Level 1 hy­po­glycemia is defined as a mea­sur­able glu­cose con­cen­tra­tion <70 mg/dL (3.9 mmol/‍L) but ≥54 mg/dL (3.0 mmol/‍L). A blood glu­cose con­cen­tra­tion of 70 mg/dL (3.9 mmol/‍L) has been rec­og­nized as a thresh­old for neu­roen­docrine re­sponses to falling glu­cose in peo­ple with­out di­a­betes. Be­cause many peo­ple with di­a­betes demon­strate im­paired coun­ter­reg­u­la­to­ry re­sponses to hy­po­glycemia and/‍or ex­pe­ri­ence hy­po­glycemia un­aware­ness, a mea­sured glu­cose level <70 mg/dL (3.9 mmol/‍L) is con­sid­ered clin­i­cally im­por­tant, inde­pendent of the sever­i­ty of acute hy­po­glyce­mic symp­toms. Level 2 hy­po­glycemia (defined as a blood glu­cose con­cen­tra­tion <54 mg/dL [3.0 mmol/‍L]) is the thresh­old at which neu­ro­gly­copenic symp­toms begin to occur and re­quires im­me­di­ate ac­tion to re­solve the hy­po­glyce­mic event. Last­ly, level 3 hy­po­glycemia is defined as a se­vere event char­ac­ter­ized by al­tered men­tal and/‍or phys­i­cal func­tioning that re­quires as­sis­tance from an­oth­er per­son for re­cov­ery. Stud­ies of rates of level 3 hy­po­glycemia that rely on claims data for hos­pi­tal­iza­tion, emer­gen­cy de­part­ment vis­its, and am­bu­lance use sub­stan­tial­ly un­der­es­ti­mate rates of level 3 hy­po­glycemia (45), yet find high bur­den of hy­po­glycemia in adults over 60 years of age in the com­mu­ni­ty (46). African Amer­i­cans are at sub­stan­tial­ly in­creased risk of level 3 hy­po­glycemia (46,47). In ad­di­tion to age and race, other im­por­tant risk fac­tors found in a com­mu­ni­ty-‍based epi­demi­o­log­ic co­hort of older black and white adults with type 2 di­a­betes in­clude in­sulin use, poor or mod­er­ate ver­sus good glycemic con­trol, al­bu­min­uria, and poor cog­ni­tive func­tion (46).

Symp­toms of hy­po­glycemia in­clude, but are not lim­it­ed to, shak­i­ness, ir­ri­tabil­i­ty, con­fu­sion, tachy­car­dia, and hunger. Hy­po­glycemia may be in­con­ve­nient or fright­en­ing to pa­tients with di­a­betes. Level 3 hy­po­glycemia may be rec­og­nized or unrec­og­nized and can progress to loss of con­sciousness, seizure, coma, or death. It is re­versed by ad­min­is­tra­tion of rapid-‍act­ing glu­cose or glucagon. Hy­po­glycemia can cause acute harm to the per­son with di­a­betes or oth­ers, es­pe­cial­ly if it caus­es falls, motor ve­hi­cle ac­ci­dents, or other in­jury. A large co­hort study sug­gested that among older adults with type 2 di­a­betes, a his­to­ry of level 3 hy­po­glycemia was as­so­ci­at­ed with greater risk of de­men­tia (48). Con­verse­ly, in a sub­study of the AC­CORD trial, cog­ni­tive im­pair­ment at base­line or de­cline in cog­ni­tive func­tion dur­ing the trial was significant­ly as­so­ci­at­ed with sub­se­quent episodes of level 3 hy­po­glycemia (49). Ev­i­dence from DCCT/EDIC, which in­volved ado­les­cents and younger adults with type 1 di­a­betes, found no as­so­ci­a­tion be­tween fre­quen­cy of level 3 hy­po­glycemia and cog­ni­tive de­cline (50), as dis­cussed in Sec­tion 13 “Chil­dren and Ado­les­cents.”

Level 3 hy­po­glycemia was as­so­ci­at­ed with mor­tal­i­ty in par­tic­i­pants in both the stan­dard and the in­ten­sive glycemia arms of the AC­CORD trial, but the re­la­tion­ships be­tween hy­po­glycemia, achieved A1C, and treat­ment in­ten­si­ty were not straight-‍for­ward. An as­so­ci­a­tion of level 3 hy­po­glycemia with mor­tal­i­ty was also found in the AD­VANCE trial (51). An as­so­ci­a­tion be­tween self-‍re­port­ed level 3 hy­po­glycemia and 5-year mor­tal­i­ty has also been re­port­ed in clin­i­cal prac­tice (52).

Young chil­dren with type 1 di­a­betes and the el­der­ly, in­clud­ing those with type 1 and type 2 di­a­betes (48,53), are noted as par­tic­u­lar­ly vul­ner­a­ble to hy­po­glycemia be­cause of their re­duced abil­i­ty to rec­og­nize hy­po­glyce­mic symp­toms and ef­fec­tively com­mu­ni­cate their needs. In­di­vid­u­al­ized glu­cose tar­gets, pa­tient ed­u­ca­tion, di­etary in­ter­ven­tion (e.g., bed­time snack to pre­vent overnight hy­po­glycemia when specifically need­ed to treat low blood glu­cose), ex­er­cise man­age­ment, med­i­ca­tion ad­just­ment, glu­cose mon­i­tor­ing, and rou­tine clin­i­cal surveil­lance may im­prove pa­tient out­comes (54). CGM with au­to­mat­ed low glu­cose sus­pend has been shown to be ef­fec­tive in re­duc­ing hy­po­glycemia in type 1 di­a­betes (55). For pa­tients with type 1 di­a­betes with level 3 hy­po­glycemia and hy­po­glycemia un­aware­ness that per­sists de­spite med­i­cal treat­ment, human islet trans­plan­ta­tion may be an op­tion, but the ap­proach re­mains experimen­tal (56,57).

In 2015, the ADA changed its prepran­di­al glycemic tar­get from 70–130 mg/dL (3.9–7.2 mmol/‍L) to 80–130 mg/dL (4.4–7.2 mmol/‍L). This change reflects the re­sults of the ADAG study, which demon­strat­ed that high­er glycemic tar­gets cor­re­spond­ed to A1C goals (7). An ad­di­tional goal of rais­ing the lower range of the glycemic tar­get was to limit overtreat­ment and pro­vide a safe­ty mar­gin in pa­tients titrat­ing glu­cose-‍low­er­ing drugs such as in­sulin to glycemic tar­gets.

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5.2.0.0 Hy­po­glycemia Treat­ment

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5.2.1.0 Overview

Providers should con­tin­ue to coun­sel pa­tients to treat hy­po­glycemia with fast-‍act­ing car­bo­hy­drates at the hy­po­glycemia alert value of 70 mg/dL (3.9 mmol/‍L) or less. Hy­po­glycemia treat­ment re­quires in­ges­tion of glu­cose-‍ or car­bo­hy­drate-containing foods. The acute glycemic re­sponse cor­re­lates bet­ter with the glu­cose con­tent of food than with the car­bo­hy­drate con­tent of food. Pure glu­cose is the pre­ferred treat­ment, but any form of car­bo­hy­drate that con­tains glu­cose will raise blood glu­cose. Added fat may re­tard and then pro­long the acute glycemic re­sponse. In type 2 di­a­betes, in­gest­ed pro­tein may in­crease in­sulin re­sponse with­out in­creas­ing plas­ma glu­cose con­cen­tra­tions (58). There­fore, car­bo­hy­drate sources high in pro­tein should not be used to treat or pre­vent hy­po­glycemia. On­go­ing in­sulin ac­tiv­i­ty or in­sulin sec­re­t­a­gogues may lead to recur­rent hy­po­glycemia un­less more food is in­gest­ed after re­cov­ery. Once the glu­cose re­turns to nor­mal, the in­di­vid­u­al should be coun­seled to eat a meal or snack to pre­vent recur­rent hy­po­glycemia.

5.2.2.0 Glucagon

The use of glucagon is in­di­cat­ed for the treat­ment of hy­po­glycemia in peo­ple un­able or un­will­ing to con­sume car­bo­hy­drates by mouth. Those in close con­tact with, or hav­ing cus­to­di­al care of, peo­ple with hy­po­glycemia-‍prone di­a­betes (fam­i­ly mem­bers, room­mates, school per­son­nel, child care pro­viders, cor­rec­tion­al in­sti­tu­tion staff, or cowork­ers) should be in­struct­ed on the use of glucagon kits, in­clud­ing where the kit is and when and how to ad­min­is­ter glucagon. An in­di­vid­u­al does not need to be a health care pro­fes­sion­al to safe­ly ad­min­is­ter glucagon. Care should be taken to en­sure that glucagon kits are not ex­pired.

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5.3.0.0 Hy­po­glycemia Pre­ven­tion

Hy­po­glycemia pre­vention is a crit­i­cal com­po­nent of di­a­betes man­age­ment. SMBG and, for some pa­tients, CGM are es­sen­tial tools to as­sess ther­a­py and de­tect in­cip­i­ent hy­po­glycemia. Pa­tients should un­der­stand sit­u­a­tions that in­crease their risk of hy­po­glycemia, such as when fast­ing for tests or pro­ce­dures, when meals are de­layed, dur­ing and after the con­sump­tion of al­co­hol, dur­ing and after in­tense ex­er­cise, and dur­ing sleep. Hy­po­glycemia may in­crease the risk of harm to self or oth­ers, such as with driv­ing. Teach­ing peo­ple with di­a­betes to bal­ance in­sulin use and car­bo­hy­drate in­take and ex­er­cise are nec­es­sary, but these strate­gies are not al­ways sufficient for pre­vention.

In type 1 di­a­betes and se­verely in­sulindeficient type 2 di­a­betes, hy­po­glycemia un­aware­ness (or hy­po­glycemia-‍as­so­ci­at­ed au­to­nom­ic fail­ure) can se­verely com­pro­mise strin­gent di­a­betes con­trol and qual­i­ty of life. This syn­drome is char­ac­ter­ized by deficient coun­ter­reg­u­la­to­ry hor­mone re­lease, es­pe­cial­ly in older adults, and a di­min­ished au­to­nom­ic re­sponse, which both are risk fac­tors for, and caused by, hy­po­glycemia. A corol­lary to this “vi­cious cycle” is that sev­er­al weeks of avoid­ance of hy­po­glycemia has been demon­strat­ed to im­prove coun­ter­reg­u­la­tion and hy­po­glycemia aware­ness in many pa­tients (59). Hence, pa­tients with one or more episodes of clin­i­cally significant hy­po­glycemia may benefit from at least short-‍term re­lax­ation of glycemic tar­gets.

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6.0.0.0 IN­TER­CUR­RENT ILL­NESS

For fur­ther in­for­ma­tion on man­age­ment of pa­tients with hy­per­glycemia in the hos­pi­tal, please refer to Sec­tion 15 “Di­a­betes Care in the Hos­pi­tal.

Stress­ful events (e.g., ill­ness, trau­ma, surgery, etc.) may wors­en glycemic con­trol and pre­cip­i­tate di­a­bet­ic ke­toaci­do­sis or non­ke­tot­ic hy­per­glycemic hy­per­os­mo­lar state, life-‍threat­en­ing con­di­tions that re­quire im­me­di­ate med­i­cal care to pre­vent com­pli­ca­tions and death. Any con­di­tion lead­ing to de­te­ri­o­ra­tion in glycemic con­trol ne­ces­si­tates more fre­quent mon­i­tor­ing of blood glu­cose; ke­to­sis-‍prone pa­tients also re­quire urine or blood ke­tone mon­i­tor­ing. If ac­com­pa­nied by ke­to­sis, vom­it­ing, or al­ter­ation in the level of con­sciousness, marked hy­per­glycemia re­quires tem­po­rary ad­just­ment of the treat­ment reg­i­men and im­me­di­ate interac­tion with the di­a­betes care team. The pa­tient treat­ed with nonin­sulin ther­a­pies or med­i­cal nu­tri­tion ther­a­py alone may re­quire in­sulin. Ad­e­quate fluid and caloric in­take must be en­sured. In­fec­tion or de­hy­dra­tion is more like­ly to ne­ces­si­tate hos­pi­tal­iza­tion of the per­son with di­a­betes than the per­son with­out di­a­betes.

A physi­cian with ex­pertise in di­a­betes man­age­ment should treat the hos­pi­talized pa­tient. For fur­ther in­for­ma­tion on the man­age­ment of di­a­bet­ic ke­toaci­do­sis and the non­ke­tot­ic hy­per­glycemic hy­per­os­mo­lar state, please refer to the ADA con­sen­sus re­port “Hy­per­glycemic Crises in Adult Pa­tients With Di­a­betes” (60).

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7.0.0.0 Ref­er­ences

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18. Lachin JM, Genuth S, Cleary P, Davis MD, Nathan DM; Di­a­betes Con­trol and Com­pli­ca­tions Trial/‍Epi­demi­ol­o­gy of Di­a­betes In­ter­ven­tions and Com­pli­ca­tions Re­search Group. Retinopa­thy and nephropa­thy in pa­tients with type 1 di­a­betes four years after a trial of in­ten­sive ther­a­py [pub­lished cor­rec­tion ap­pears in N Engl J Med 2000;342:1376]. N Engl J Med 2000;342:381–389

19. Ohkubo Y, Kishikawa H, Araki E, et al. In­ten­sive in­sulin ther­a­py pre­vents the pro­gres­sion of di­a­bet­ic mi­crovas­cu­lar com­pli­ca­tions in Japanese pa­tients with non-in­sulin-de­pendent di­a­betes mel­li­tus: a ran­dom­ized prospec­tive 6-year study. Di­a­betes Res Clin Pract 1995;28: 103–117

20. UK Prospec­tive Di­a­betes Study (UKPDS) Group. Ef­fect of in­ten­sive blood-‍glu­cose con­trol with met­formin on com­pli­ca­tions in over­weight pa­tients with type 2 di­a­betes (UKPDS 34). Lancet 1998;352:854–865

21. UK Prospec­tive Di­a­betes Study (UKPDS) Group. In­ten­sive blood-‍glu­cose con­trol with sulpho­ny­lureas or in­sulin com­pared with con­ven­tion­al treat­ment and risk of com­pli­ca­tions in pa­tients with type 2 di­a­betes (UKPDS 33). Lancet 1998;352:837–853

22. Hol­man RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year fol­low-‍up of in­ten­sive glu­cose con­trol in type 2 di­a­betes. N Engl J Med 2008;359:1577–1589

23. Adler AI, Strat­ton IM, Neil HAW, et al. As­so­ci­a­tion of sys­tolic blood pres­sure with macrovas­cu­lar and mi­crovas­cu­lar com­pli­ca­tions of type 2 di­a­betes (UKPDS 36): prospec­tive ob­ser­va­tion­al study. BMJ 2000;321:412–419

24. Duck­worth W, Abraira C, Moritz T, et al.; VADT In­ves­ti­ga­tors. Glu­cose con­trol and vas­cu­lar com­pli­ca­tions in vet­er­ans with type 2 di­a­betes. N Engl J Med 2009;360:129–139

25. Patel A, MacMa­hon S, Chalmers J, et al.; AD­VANCE Col­lab­o­ra­tive Group. In­ten­sive blood glu­cose con­trol and vas­cu­lar out­comes in pa­tients with type 2 di­a­betes. N Engl J Med 2008; 358:2560–2572

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27. Ger­stein HC, Miller ME, By­ing­ton RP, et al.; Ac­tion to Con­trol Car­dio­vas­cu­lar Risk in Di­a­betes Study Group. Ef­fects of in­ten­sive glu­cose low­er­ing in type 2 di­a­betes. N Engl J Med 2008; 358:2545–2559

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30. Or­chard TJ, Nathan DM, Zin­man B, et al.; Writ­ing Group for the DCCT/EDIC Re­search Group. As­so­ci­a­tion be­tween 7 years of in­ten­sive treat­ment of type 1 di­a­betes and long-‍term mor­tal­i­ty. JAMA 2015;313:45–53

31. Skyler JS, Bergen­stal R, Bonow RO, et al.; Amer­i­can Di­a­betes As­so­ci­a­tion; Amer­i­can

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32. Zoun­gas S, Chalmers J, Neal B, et al.; AD­VANCE-‍ON Col­lab­o­ra­tive Group. Fol­low-‍up of blood-‍pres­sure low­er­ing and glu­cose con­trol in type 2 di­a­betes. N Engl J Med 2014;371:1392– 1406

33. Hay­ward RA, Reav­en PD, Wi­ita­la WL, et al.; VADT In­ves­ti­ga­tors. Fol­low-‍up of glycemic con­trol and car­dio­vas­cu­lar out­comes in type 2 di­a­betes. N Engl J Med 2015;372:2197–2206

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35. Duck­worth WC, Abraira C, Moritz TE, et al.; In­ves­ti­ga­tors of the VADT. The du­ra­tion of di­a­betes af­fects the re­sponse to in­ten­sive glu­cose con­trol in type 2 sub­jects: the VA Di­a­betes Trial. J Di­a­betes Com­pli­ca­tions 2011;25:355–361

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