Self-reported non-severe hypoglycaemic events in Europe

Resea ch: Complica ions Sel - epo ed non-se e e hypoglycaemic e en s in Eu ope C. G. O ¨s enson 1 , P. Geelhoed-Duij es ijn 2 , J. Lah ela 3 , R. Wei gasse 4,5 , M. Ma ke Jensen 6 and U. Pede sen-Bje gaa d 7 1 Depa men o Molecula Medicine and Su ge y, Ka olinska Ins i u e , S ockholm, Sweden, 2 Depa men o In e nal Medicine, Medical Cen e Haaglanden, The Hague, Ne he lands, 3 Depa men o Medicine, Uni e si y o Tampe e, Tampe e, Finland, 4 Depa men o In e nal Medicine, Diakonissen Hospi al Salzbu g, Salzbu g, Aus ia, 5 Depa men o In e nal Medicine, Salzbu g Gene al Hospi al, Pa acelsus Medical Uni e si y Salzbu g, Salzbu g, Aus ia, 6 No o No disk Scandina ia AB, Copenhagen, Denma k and 7 Depa men o Ca diology, Neph ology and Endoc inology, Hille ød Uni e si y Hospi al, Denma k Accep ed 18 June 2013 Abs ac Aims Hypoglycaemia p esen s a ba ie o op imum diabe es managemen bu da a a e limi ed on he equency o hypoglycaemia inciden s ou side o clinical ials. The p esen s udy in es iga ed he a es o sel - epo ed non-se e e hypoglycaemic e en s, hypoglycaemia awa eness and physician discussion o e en s in people wi h Type 1 diabe es melli us o insulin- ea ed Type 2 diabe es melli us. Me hods People in se en Eu opean coun ies aged >15 yea s wi h Type 1 diabe es o insulin– ea ed Type 2 diabe es (basal-only, basal-bolus and o he insulin egimens) we e ec ui ed ia consume panels, nu ses, elephone ec ui men and amily e e als. Responden s comple ed ou online ques ionnai es. The i s ques ionnai e collec ed backg ound in o ma ion on demog aphics and hypoglycaemia- ela ed beha iou , whils all ou ques ionnai es collec ed da a on non-se e e hypoglycaemic e en s in he p eceding 7 days. Resul s Analysis was based on 11 440 esponden -weeks om 3827 esponden s. All pa icipan s comple ed he i s ques ionnai e and 57% comple ed all ou . The mean numbe o e en s/ esponden –week was 1.8 (Type 1 diabe es) and 0.4–0.7 (Type 2 diabe es, wi h di e en insulin ea men s) co esponding o annual e en a es o 94 and 21–36, espec i ely. A o al o 63% o esponden s wi h Type 1 diabe es and 49–64% o esponden s wi h Type 2 diabe es, ea ed wi h di e en insulin egimens, who expe ienced hypoglycaemic e en s, epo ed impai ed hypoglycaemia awa eness o unawa eness. A high p opo ion o esponden s a ely o ne e in o med hei gene al p ac i ione / specialis abou hypoglycaemia: 65% (Type 1 diabe es) and 50–59% (Type 2 diabe es). O e all, 16% o esponden s wi h Type 1 diabe es and 26% o esponden s wi h Type 2 diabe es epo ed no being asked abou hypoglycaemia du ing ou ine appoin men s. Conclusion Non-se e e hypoglycaemic e en s a e common amongs people wi h Type 1 diabe es and insulin– ea ed Type 2 diabe es in eal-wo ld se ings. Many a ely o ne e in o m hei gene al p ac i ione /specialis abou hei hypoglycaemia and he eal bu den o hypoglycaemia may be unde es ima ed. Diabe . Med. 31, 92–101 (2014) In oduc ion The goal o diabe es managemen o people wi h Type 1 o Type 2 diabe es melli us is o main ain no moglycaemia so as o educe diabe ic complica ions and he isk o mo ali y; howe e , he in ensi ica ion o he apy o achie e his goal may inc ease he incidence o hypoglycaemic episodes. Hypoglycaemia emains a common and unp edic able side e ec o insulin he apy, and has a nega i e physical and emo ional impac on people wi h diabe es [1]. Hypoglycae- mic episodes a e cha ac e ized as ei he se e e o non-se e e acco ding o whe he assis ance is equi ed om ano he indi idual, o whe he he pe son wi h diabe es can manage he e en alone, espec i ely [2,3]. Non-se e e hypoglycae- mic e en s accoun o 88–98% o all hypoglycaemic e en s Co espondence o: M. Ma ke Jensen. E-mail: mm j@no ono disk.com This pape was p e iously p esen ed as ollows: O ¨s enson CG, Geelhoed-Duij es ijn PH, Jensen MM, Pede sen-Bje gaa d U. Pa ien - epo ed hypoglycaemia in eal-wo ld se ings in se en Eu opean coun ies. ISPOR 15 h Annual Eu opean Cong ess 2012 A277 DB4. This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial License, which pe mi s use, dis ibu ion and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed and is no used o comme cial pu poses. 92 ª2013 The Au ho s. Diabe ic Medicine published by John Wiley & Sons L d on behal o Diabe es UK. DIABETICMedicine DOI: 10.1111/dme.12261 [4–6] and ha e been shown o a ec unc ioning [7], heal h- ela ed quali y o li e [4,8], heal hca e esou ce use [4] and wo k p oduc i i y [7]. Fu he mo e, hypoglycaemia p esen s a signi ican ba ie o op imum diabe es manage- men , as ea o hypoglycaemic e en s may cause exagge a ed a oidance beha iou and consequen ly subop imum insulin he apy and poo glycaemic con ol [9,10]. Whils he impo ance o educa ion abou he ecogni ion and ea men o hypoglycaemia is acknowledged in he cu en Eu opean Associa ion o he S udy o Diabe es and Ame ican Diabe es Associa ion consensus s a emen [11], he eal-wo ld le els o communica ion be ween heal hca e p o essionals and people wi h diabe es ega ding hypoglycaemia a e no ully unde - s ood. Da a on he equency o hypoglycaemia, speci ically non-se e e hypoglycaemic e en s, ou side o clinical ial se ings a e limi ed and a ied [1,5,6,8]. The a iabili y o da a is p obably a ibu able o di e ing s udy popula ions (deg ee o selec ion, Type 1 diabe es and/o insulin- ea ed Type 2 diabe es), a ge s o glycaemic con ol, du a ion o ea men , me hods o da a collec ion and coun y co e age wi hin hese s udies. Ou aim was o in es iga e he eal-wo ld equency o sel - epo ed non-se e e hypoglycaemic e en s, le els o impai ed hypoglycaemia awa eness and discussion o hypo- glycaemic e en s wi hin physician consul a ions. We used a mul i-coun y ques ionnai e-based su ey in a la ge non- in e en ional coho o people wi h Type 1 diabe es o insulin- ea ed Type 2 diabe es. The ques ionnai e also explo ed he heal h- ela ed impac and economic bu den o hypoglycaemia, he esul s o which a e o be p o ided in a ollow-on publica ion. Subjec s and me hods The ques ionnai e-based su ey was conduc ed be ween No embe 2011 and May 2012 and ec ui ed esponden s om Aus ia, Denma k, Finland, No way, Sweden, Swi ze - land and he Ne he lands. Responden s we e p ima ily ec ui ed ia exis ing la ge consume panels ha we e es ablished o e lec a ep esen a i e sample o he gene al diabe es popula ion, based on age, gende and o he demo- g aphic cha ac e is ics. Whe e su icien numbe s o espon- den s could no be iden i ied ia consume panels, o he me hods o ec ui men we e ini ia ed, including he use o ad e isemen s on diabe es- ela ed websi es and pa ien associa ion websi es (wi h a link o he sc eene o inclusion in he su ey), ace- o- ace ec ui men , elephone ec ui - men and subsequen e e als om iends/ amily. In addi- ion, some esponden s we e di ec ly ec ui ed a gene al p ac i ione clinics by nu ses who we e asked o iden i y pa icipan s and seek consen o pa icipa ion, be o e p o iding con ac de ails o hose eligible o ake pa in he su ey. All esponden s comple ed a sc eening s age o de e mine eligibili y o s udy inclusion. Be o e s udy en y, esponden s we e unawa e ha he su ey ela ed o hypo- glycaemia. A a ge o 600 esponden s pe coun y was se wi h an expec a ion ha he p obabili y o a hypoglycaemic e en would ha e a 95% CI o 4%. The inclusion c i e ia we e a diagnosis o ei he Type 1 diabe es o Type 2 diabe es om a heal hca e p o essional, cu en insulin ea men and age >15 yea s. In addi ion, esponden s we e equi ed o ead and speak he na i e language o he coun y in which hey esided and ha e an email add ess in o de o comple e he ques ionnai e online. Responden s we e o e ed a small incen i e o comple ion o he en i e su ey (€5–25), in line wi h cu en ma ke esea ch guidelines and o ensu e he e was no undue incen i e o pa icipa e. All esponden s we e anonymous acco ding o he egula ions and p ac ice o he ma ke esea ch go e ning bodies, he Eu opean Socie y o Opinion and Ma ke ing Resea ch [12] and he Eu opean Pha maceu- ical Ma ke Resea ch Associa ion [13]. Eligible esponden s we e in i ed by email o comple e an online ques ionnai e, in ou wa es. They ecei ed in i a- ions o he second, hi d and ou h ques ionnai es 7 days a e hey had comple ed he p e ious ques ionnai e. Ques ionnai es we e adap ed om hose used in a p e ious s udy [7], which had been designed using insigh s collec ed du ing ocus g oups on he impac o hypoglycaemia epo ed by people wi h diabe es [14]. Da a collec ed in he i s ques ionnai e included esponden demog aphics, p e ious expe ience wi h and awa eness o hypoglycaemia, he impac o hypoglycaemia and he numbe o non-se e e hypoglycaemic e en s and se e e hypoglycaemic e en s. Wha ’s new? •Limi ed da a exis on he equency o non-se e e hypoglycaemic e en s in people wi h Type 1 o Type 2 diabe es in eal-wo ld p ac ice, as non-se e e hypogly- caemic e en s, by de ini ion, do no equi e heal hca e p o essional in e ac ions (a e no ou inely egis e ed). •The equency o non-se e e hypoglycaemic e en s in eal-wo ld p ac ice may di e om ha obse ed in clinical ials because o he cha ac e is ics o clinical ial designs. •To ou knowledge, his is he i s s udy epo ing he equency o non-se e e hypoglycaemic e en s in eal-- wo ld p ac ice in he se en coun ies in ol ed in ou s udy. •Non-se e e hypoglycaemic e en s a e common amongs people wi h Type 1 o insulin- ea ed Type 2 diabe es. •Many people wi h diabe es a ely o ne e in o m hei gene al p ac i ione /specialis abou hei hypoglyca- emia and he eal bu den may be unde es ima ed. ª2013 The Au ho s. Diabe ic Medicine published by John Wiley & Sons L d on behal o Diabe es UK. 93 Resea ch a icle DIABETICMedicine Responden s we e also asked abou hypoglycaemia- ela ed discussions du ing gene al p ac i ione /specialis consul a- ions. Responden s who had expe ienced a non-se e e hypoglycaemic e en we e asked whe he hey no mally in o med hei gene al p ac i ione /specialis a e hey had had a hypoglycaemic e en . A non-se e e hypoglycaemic e en was de ined as symp oms o hypoglycaemia (e.g. swea ing, shaking, headache) wi h o wi hou a blood glucose measu emen , o a low blood glucose measu emen (≤3.1 mmol/L) wi hou symp oms, ha he indi idual managed wi hou assis ance om ano he pe son. A se e e hypoglycaemic e en was de ined as an e en o low blood glucose le el needing help om a hi d pa y o manage (e.g. help om a amily membe o a heal hca e p o essional, including eme gency oom isi s and hospi aliza ion). Ques- ions also e e ed o non-se e e hypoglycaemic e en s occu ing du ing he day ime o he nigh - ime (while he esponden was in bed/asleep). The subsequen ques ion- nai es ocused only on he numbe o non-se e e hypogly- caemic e en s and he impac o hese e en s. Comple ion o he su ey in ou wa es p o ided da a o he numbe o non-se e e hypoglycaemic e en s occu ing o e he pas 4 weeks, whils minimizing he ecall pe iod (i.e. ou 7-day pe iods we e epo ed). The es ima ed o al amoun o ime o comple e all ou ques ionnai es was 35 min. Ques ion- nai es we e comple ed anonymously bu esponses could be acked ac oss he ou wa es by an iden i ica ion numbe assigned a s udy ini ia ion. Limi s o uppe and lowe en y alues we e included wi hin he ques ionnai e o minimize e oneous alues. In addi ion, da a we e cleaned using a logical consis ency check ha allowed he emo al o indi idual answe s o which inco ec calcula ions had been made by a esponden (e.g. whe e longe ea men du a ion han diabe es du a ion was epo ed), o he emo al o he esponden om he en i e analysis in ins ances whe e ype o diabe es was no known o whe e e oneous epo ing o simple demog aphic a iables occu ed (e.g. diabe es du a ion longe han cu en age). The a e o non-se e e hypoglycaemic e en s was calcula ed using da a om all esponden s who comple ed a leas one wa e o he su ey. The i s ques ionnai e collec ed da a o non-se e e hypoglycaemic e en s in he las 4 weeks and he las 7 days. All subsequen wa es epo ed only he numbe o non-se e e hypoglycaemic e en s in he las 7 days, so he es ima ed weekly a es om he 4-week a e p o ided in wa e one could be ma ched wi h he weekly a es epo ed by he ou imes 7-day a es ac oss wa es one, wo, h ee and ou . Annual e en a es we e calcula ed using he subsequen wa e mean e en a e pe esponden -week mul iplied by 52. The ela ionships be ween demog aphic ac o s and he annual a e o non-se e e hypoglycaemic e en s we e analysed in eg ession models. The con inuous dependen a iable o he annual e en a e was es ima ed by combining wo a iables: he 4-weekly non-se e e hypoglycaemia e en a e and, o esponden s who did no expe ience a hypoglycaemic e en in he p e ious 4 weeks, answe s o he ques ion, ‘How o en do you no mally ha e non-se e e hypoglycaemic e en s?’ This analysis used da a collec ed du ing he i s wa e o he su ey. Analysis on Type 1 and Type 2 diabe es was ca ied ou sepa a ely. Reg ession analyses we e conduc ed o he whole s udy popula ion, as he s udy was no designed o c oss-coun y compa isons. The classi ica ion sys em o awa eness o hypoglycaemia was based on a p ospec i ely alida ed s udy by Pede sen- Bje gaa d e al. 2003 [15]. Any esponden who answe ed ‘some imes’ o ‘ne e ’ o he ques ion, ‘Can you eel when you blood suga is low?’ was classi ied as being unawa e o hypoglycaemia, hose who answe ed ‘usually’ we e classi ied as ha ing impai ed awa eness and hose who answe ed ‘always’ we e classi ied as awa e. S anda d desc ip i e me hods (means/pe cen age and s an- da d de ia ions) we e used o epo esul s o esponden s in he ollowing ou g oups: people wi h Type 1 diabe es, people wi h Type 2 diabe es ecei ing basal-only/long-ac ing insulin-only he apy, people wi h Type 2 diabe es ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy, o people wi h Type 2 diabe es ecei ing ano he o m o insulin he apy. Compa isons we e pe o med using - es s and a P alue <0.05 was conside ed o indica e s a is ical signi icance. Resul s A o al o 3959 esponden s ac oss se en coun ies we e ec ui ed o he s udy and 132 (3.3%) we e excluded as a esul o inadequa e ques ionnai e comple ion. The emaining 3827 esponden s comple ed he ini ial su ey, wi h 76, 66 and 57% comple ing wa es wo, h ee and ou , espec i ely, esul ing in a o al o 11 440 esponden -week eco ds. The demog aphics o esponden s wi h Type 1 diabe es and hose wi h Type 2 diabe es a e shown in Table 1 and we e simila ac oss coun ies (da a no shown). Di e ences be ween esponden s wi h Type 1 diabe es and esponden s wi h Type 2 diabe es we e consis en wi h hose expec ed (age, diabe es du a ion e c.). Age and BMI we e nega i ely co ela ed wi h he annual a e o non–se e e hypoglycaemic e en s (P<0.05). Female gende and du a ion o insulin ea men we e posi i ely co ela ed wi h he annual e en a e (P<0.05). The mean sel - epo ed non-se e e hypoglycaemic e en a e was 1.8 pe esponden -week o esponden s wi h Type 1 diabe es and 0.5 o esponden s wi h Type 2 diabe es (Table 2). Indi idual coun y da a a e also epo ed in Table 2. Ra es o esponden s wi h Type 2 diabe es we e 0.4 ( esponden s ecei ing basal-only/long-ac ing insulin-only he apy), 0.7 ( esponden s ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy) and 0.5 ( esponden s ecei ing ano he o m o insulin he apy; Table 2). The calcula ed mean annual e en a es we e he e o e 91.0, 20.3, 35.4 and 27.0 in he ou g oups (Table 2). The 94 ª2013 The Au ho s. Diabe ic Medicine published by John Wiley & Sons L d on behal o Diabe es UK. DIABETICMedicine Sel - epo ed non-se e e hypoglycaemic e en s in Eu ope C. G. € Os enson e al. p opo ion o noc u nal non-se e e hypoglycaemic e en s we e sligh ly g ea e in esponden s wi h Type 2 diabe es han in esponden s wi h Type 1 diabe es: 22% (Type 1 diabe es), 32% ( esponden s wi h Type 2 diabe es ecei ing basal-only/long-ac ing insulin-only he apy), 22% ( espon- den s wi h Type 2 diabe es ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy) and 27% ( esponden s wi h Type 2 diabe es ecei ing ano he o m o insulin he apy; Table 2). Fou -week non-se e e hypoglycaemic e en a es ecalled by esponden s in ques ionnai e one we e simila o, al hough sligh ly lowe han, hose collec ed o e he ou wa es o he s udy (Table 2). The mean numbe o sel - epo ed se e e hypoglycaemic e en s expe ienced in he las yea was 0.7 o esponden s wi h Type 1 diabe es, 0.1 o esponden s wi h Type 2 diabe es ecei ing basal-only/long-ac ing insulin-only he - apy, 0.2 o esponden s wi h Type 2 diabe es ecei ing basal-bolus /bo h sho - and long-ac ing insulin he apy and 0.2 o esponden s wi h Type 2 diabe es ecei ing ano he o m o insulin he apy (Table 2). O e all, 76% o s udy esponden s (87% o esponden s wi h Type 1 and 59–78% o esponden s wi h Type 2 diabe es) had p e iously expe ienced a hypoglycaemic e en a any poin (i.e. no jus in he s udy ecall pe iod). In esponden s who had p e ious expe ience o hypoglycaemic e en s, impai ed awa eness was epo ed by 53% o espon- den s wi h Type 1 diabe es, 45% o esponden s wi h Type 2 diabe es ecei ing basal-only/long-ac ing insulin he apy only, 43% o esponden s wi h Type 2 diabe es ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy and 43% o esponden s wi h Type 2 diabe es ecei ing ano he o m o insulin he apy (Table 3). A u he 10, 19, 6 and 8% we e classi ied as unawa e o each esponden ype, espec i ely. Responden s wi h Type 1 diabe es who we e unawa e had signi ican ly highe a es o non-se e e hypo- glycaemic e en s han hose who we e always awa e (P<0.05; Table 3). Among esponden s wi h Type 2 diabe es ecei ing basal-only/long-ac ing insulin-only he - apy and esponden s wi h Type 2 diabe es ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy, esponden s wi h impai ed awa eness had signi ican ly highe non-se e e hypoglycaemic e en a es han hose who we e awa e (P<0.05). In esponden s wi h Type 2 diabe es ecei ing ano he o m o insulin he apy, signi - ican ly lowe non-se e e hypoglycaemic e en a es we e obse ed in unawa e esponden s han in esponden s who we e always awa e (P<0.05; Table 3). Signi ican ly highe a es o se e e hypoglycaemic e en s we e epo ed by esponden s wi h Type 1 diabe es classi ied ei he as unawa e o as ha ing impai ed awa eness, compa ed wi h awa e esponden s (P<0.05). A high p opo ion o esponden s who had expe ienced a non-se e e hypoglycaemic e en s a ed ha hey ‘ a ely’ o ‘ne e ’ in o med hei gene al p ac i ione /specialis abou hei hypoglycaemia: 65% ( esponden s wi h Type 1 Table 1 Responden - ela ed cha ac e is ics Type 1 diabe es Type 2 diabe es Numbe o esponden s, n(%) 1631 (43) 2196 (57) Mean (SD) age*44.3 (14.1) 60.3 (10.7) Gende , emale, n(%) † 722 (44) 735 (33) Educa ion, n(%) ‡ P ima y school 244 (15) 393 (18) High school 808 (49) 1147 (52) Uni e si y (plus PhD. o highe ) 517 (32) 558 (25) O he 62 (4) 98 (5) Mean (SD) BMI*25.87 (4.88) 31.54 (6.39) Smoking, n(%) § Smoke 458 (28) 450 (20) Ex-smoke 418 (26) 1008 (46) Non-smoke 755 (46) 738 (34) Diabe es du a ion, n(%) <2 yea s 20 (1) 41 (2) 2–5 yea s 220 (14) 317 (15) 5–9 yea s 145 (10) 394 (19) 10–14 yea s 197 (13) 546 (26) 15 +yea s 957 (62) 806 (38) Insulin ea men ype, n(%) ¶ Long-ac ing insulin only 134 (8) 812 (37) Bo h sho - and long-ac ing insulin 1058 (65) 942 (43) O he insulin ypes 439 (27) 442 (20) Du a ion o insulin ea men , n(%)** <2 yea s 113 (7) 311 (14) 2–5 yea s 189 (12) 741 (35) 5–9 yea s 136 (9) 394 (18) 10 +yea s 1101 (72) 659 (32) HbA 1c§ Mean mmol/mol (SD); 61 (16.1) 60 (16.9) Na ional Glycohaemoglobin S anda disa ion P og amme%, (SD) 7.7 (1.5) 7.6 (1.5) Medical complica ions, none epo ed, n(%) †† 1036 (64) 1148 (52) *Signi ican nega i e co ela ion wi h yea ly numbe o non-se e e hypoglycaemic e en s ( o bo h Type 1 diabe es and Type 2 diabe es, acco ding o eg ession analysis; P<0.05). †Signi ican posi i e co ela ion wi h yea ly numbe o non- se e e hypoglycaemic e en s ( o bo h Type 1 diabe es and Type 2 diabe es, acco ding o eg ession analysis; P<0.05). ‡Signi ican (P<0.05) nega i e co ela ion wi h yea ly numbe o non-se e e hypoglycaemic e en s (Type 2 diabe es only). §No signi ican co ela ion wi h yea ly numbe o non-se e e hypoglycaemic e en s. ¶Va iable no included in he eg ession analysis. **Du a ion o insulin ea men was co ela ed wi h diabe es du a ion, and hus du a ion o ea men was included in he eg ession analysis. A signi ican posi i e co ela ion was ound be ween du a ion o ea men and yea ly numbe o non-se e e hypoglycaemic e en s ( o bo h Type 1 diabe es and Type 2 diabe es; P<0.05). ††Medical complica ions we e co ela ed wi h age. Medical complica ions we e no signi ican ly associa ed wi h yea ly numbe o non-se e e hypoglycaemic e en s, independen o hei associa ion wi h age. Ques ionnai e op ions o medical complica ions included: None, Eye p oblems, Neu opa hy, Ca dio ascula disease, Renal disease, Ampu a ions, O he (please speci y). ª2013 The Au ho s. Diabe ic Medicine published by John Wiley & Sons L d on behal o Diabe es UK. 95 Resea ch a icle DIABETICMedicine Table 2 Sel - epo ed, ecalled a es o hypoglycaemic e en s Ra es based on 11440 w epo s om 3827 esponden s To al: N=3827; 11440 w Aus ia: n=553; 1773 w Swi ze land: n=395; 1116 w Denma k: n=601; 1894 w Finland: n=628; 1364 w Ne he lands: n=692; 2456 w No way n=379; 918 w Sweden n=579; 1919 w Mean (SD) sel - epo ed NSHE a e pe esponden pe week* Type 1 diabe es 1.8 (2.3) 1.6 (2.3) 1.4 (1.8) 1.9 (2.4) 1.3 (2.1) 2.0 (2.5) 1.8 (2.2) 2.0 (2.5) Type 2 diabe es: BOT 0.4 (1.1) 0.3 (0.8) 0.4 (0.9) 0.5 (1.5) 0.2 (0.6) 0.5 (1.2) 0.4 (1.0) 0.4 (1.1) Type 2 diabe es: BB 0.7 (1.3) 0.5 (1.1) 0.6 (1.0) 0.7 (1.6) 0.5 (1.1) 0.7 (1.2) 1.0 (1.7) 0.9 (1.7) Type 2 diabe es: O he 0.5 (1.2) 0.4 (0.8) 0.7 (1.2) 0.4 (1.0) 0.2 (0.6) 0.9 (1.7) 0.6 (1.2) 0.4 (0.7) Mean annual calcula ed NSHE a es (52 weeks)* Type 1 diabe es 91.0 84.8 73.3 98.8 67.1 105.0 93.1 106.1 Type 2 diabe es: BOT 20.3 15.1 18.7 23.4 10.4 24.4 20.3 22.4 Type 2 diabe es: BB 35.4 27.6 32.2 38.5 25.0 34.3 50.4 45.8 Type 2 diabe es: O he 27.0 18.7 36.9 21.8 12.5 44.7 29.6 18.7 P opo ion o NSHE ha occu whils sleeping, %* Type 1 diabe es 22 19 20 22 31 13 19 20 Type 2 diabe es: BOT 32 22 49 27 22 33 18 39 Type 2 diabe es: BB 22 22 28 24 33 16 26 20 Type 2 diabe es: O he 27 15 42 38 39 25 11 19 Based on all esponden s comple ing wa e 1, n=3825 Mean (SD) sel - epo ed NSHE 4 week a e † Type 1 diabe es 6.3 (8.2) 5.5 (6.9) 6.0 (7.8) 7.7 (9.3) 4.2 (7.6) 7.9 (9.1) 6.3 (8.0) 7.4 (7.6) Type 2 diabe es: BOT 1.2 (3.2) 0.7 (1.7) 0.8 (1.6) 1.6 (4.3) 0.5 (1.4) 1.5 (4.2) 1.2 (2.1) 1.5 (3.5) Type 2 diabe es: BB 2.6 (5.1) 1.6 (2.4) 2.1 (3.9) 3.1 (6.2) 1.6 (2.9) 3.1 (5.0) 2.5 (3.3) 3.5 (7.9) Type 2 diabe es: O he 1.7 (3.9) 1.3 (2.5) 0.6 (1.3) 1.4 (3.0) 0.8 (1.1) 3.4 (5.7) 2.9 (7.1) 1.5 (2.6) Based on all esponden s comple ing wa e 1, n=3820 Mean (SD) numbe o SHEs in he las yea ‡ Type 1 diabe es 0.7 (2.4) 0.7 (2.1) 0.6 (2.0) 0.6 (2.3) 0.6 (2.0) 0.9 (2.3) 1.0 (3.2) 0.9 (2.8) Type 2 diabe es: BOT 0.1 (0.8) 0.1 (0.5) 0.2 (0.6) 0.1 (0.2) 0.1 (0.3) 0.1 (0.3) 0.2 (0.6) 0.3 (1.6) Type 2 diabe es: BB 0.2 (0.8) 0.2 (0.6) 0.5 (1.4) 0.1 (0.6) 0.1 (0.3) 0.2 (0.9) 0.4 (1.4) 0.1 (0.4) Type 2 diabe es: O he 0.2 (0.8) 0.2 (0.5) 0.3 (1.1) 0.3 (1.3) 0.1 (0.4) 0.2 (0.5) 0.1 (0.3) 0.1 (0.3) w, esponden week; NSHE, non-se e e hypoglycaemic e en ; BOT, basal-only/long-ac ing insulin-only he apy; BB, basal bolus/sho - and long-ac ing insulin he apy; SHE, se e e hypoglycaemic e en ; O he , e.g. mixed insulin. *All esponden -weeks epo ed; includes all esponden s ega dless o whe he comple ing all ou ques ionnai es. †All esponden s comple ing wa e 1 ( wo esponses we e emo ed because o e oneous answe s o his ques ion). ‡All esponden s comple ing wa e 1 (se en esponses we e emo ed because o e oneous answe s o his ques ion). 96 ª2013 The Au ho s. Diabe ic Medicine published by John Wiley & Sons L d on behal o Diabe es UK. DIABETICMedicine Sel - epo ed non-se e e hypoglycaemic e en s in Eu ope C. G. € Os enson e al. diabe es), 50% ( esponden s wi h Type 2 diabe es ecei ing basal-only/long-ac ing insulin-only he apy), 59% ( espon- den s wi h Type 2 diabe es ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy) and 53% ( esponden s wi h Type 2 diabe es ecei ing ano he o m o insulin he apy; Table 4). The lowes le el o communica ion was epo ed in he Ne he lands (da a no shown). The p opo ion o esponden s in he Ne he lands who a ely o ne e in o med hei gene al p ac i ione /specialis abou hei hypoglycae- mic e en s was 86% ( esponden s wi h Type 1 diabe es), 64% ( esponden s wi h Type 2 diabe es ecei ing basal-only he apy/long-ac ing insulin-only he apy), 77% ( esponden s wi h Type 2 diabe es ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy) and 79% ( esponden s wi h Type 2 diabe es ecei ing ano he o m o insulin he apy). E en a es o non-se e e hypoglycaemic e en s we e signi ican ly highe o esponden s wi h Type 1 diabe es o Type 2 diabe es who a ely o ne e in o med a physician abou hei non-se e e hypoglycaemic e en s (P<0.05). When esponden s we e asked abou opics discussed du ing gene al p ac i ione /specialis consul a ions, 17% (Type 1 diabe es), 28% (Type 2 diabe es ecei ing basal-only/ long-ac ing insulin-only he apy), 26% (Type 2 diabe es ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy) and 21% (Type 2 diabe es ecei ing ano he o m o insulin he apy) o esponden s s a ed ha hei gene al Table 3 Sel - epo ed esponden awa eness o hypoglycaemia and co esponding e en a es in esponden s who had p e iously expe ienced a hypoglycaemic e en Responden s, N=2925* Type 1 diabe es, n=1420 Type 2 diabe es BOT, n=479 BB, n=736 O he , n=290 Can you eel when you blood suga is low? Always awa e,% 36 36 51 49 Impai ed awa eness,% 53 45 43 43 Unawa e,% 10 19 6 8 Mean (SD) NSHE a es o hose esponden s who a e awa e, ha e impai ed awa eness o a e unawa e Always awa e 1.7 (2.3) 0.5 (1.0) 0.8 (1.5) 0.7 (1.4) Impai ed awa eness 1.9 (2.2) 0.6 (1.2) † 0.9 (1.5) † 0.7 (1.2) Unawa e 2.6 (3.0) † 0.4 (1.0) 0.7 (1.1) 0.3 (0.7) † Mean (SD) SHE a es o hose esponden s who a e awa e, ha e impai ed awa eness o a e unawa e Always awa e 0.4 (1.8) 0.2 (0.6) 0.2 (0.9) 0.2 (0.5) Impai ed awa eness 0.8 (1.9) † 0.2 (1.1) 0.2 (0.7) 0.2 (1.2) Unawa e 2.7 (5.2) † 0.1 (0.5) 0.4 (1.0) 0.2 (0.5) BOT, basal-only/long-ac ing insulin-only he apy; BB, basal-bolus/sho - and long-ac ing insulin he apy; O he , e.g. mixed insulin; NSHE, non-se e e hypoglycaemic e en ; SHE,se e e hypoglycaemic e en . *All esponden s who had p e iously expe ienced a NSHE a any poin (i.e. no jus in he s udy ecall pe iod; n=2925). †P<0.05 signi icance agains always awa e. Table 4 Communica ion be ween esponden s and gene al p ac i ione s/specialis s All esponden s, N=3827* Type 1 diabe es, n=1631 Type 2 diabe es BOT, n=812 BB, n=942 O he , n=442 Gene al p ac i ione /specialis did no ask abou hypoglycaemia du ing ou ine appoin men s,%* 17 28 26 21 All esponden s who ha e e e expe ienced a NSHE, N=2925 † Type 1 diabe es, n=1420 Type 2 diabe es BOT, n=479 BB, n=736 O he , n=290 P opo ion o esponden s a ely o ne e in o ming hei gene al p ac i ione /specialis o a hypoglycaemic e en , % † 65 50 59 53 Mean (SD) NSHE a es o hose esponden s communica ing e sus hose who do no ell hei gene al p ac i ione /specialis † Always/Mos ly 1.5 (1.9) 0.4 (0.9) 0.6 (1.0) 0.6 (0.9) Ra ely/Ne e 2.2 (2.3) ‡ 0.6 (1.0) ‡ 1.0 (1.5) ‡ 0.8 (1.2) BOT, basal-only/long-ac ing insulin-only he apy; BB, basal-bolus/sho - and long-ac ing insulin he apy; O he , e.g. mixed insulin; NSHE, non-se e e hypoglycaemic e en . *All esponden s comple ing ques ionnai e one (n=3827). †All esponden s who ha e e e expe ienced a NSHE (n=2925). ‡P<0.05 signi icance. ª2013 The Au ho s. Diabe ic Medicine published by John Wiley & Sons L d on behal o Diabe es UK. 97 Resea ch a icle DIABETICMedicine p ac i ione /specialis ‘did no ask abou hypoglycaemia du ing ou ine appoin men s’ (Table 4). Discussion and conclusions This s udy cap u es he sel - epo ed, ecalled a es o non-se e e hypoglycaemic e en s and se e e hypoglycaemic e en s in bo h people wi h Type 1 diabe es and hose wi h insulin- ea ed Type 2 diabe es, and shows ha hypoglycae- mic e en s emain a common ad e se e en o insulin he apy in bo h g oups. The majo i y o he published li e a u e on hypoglycaemic e en a es includes only people wi h Type 1 diabe es, o is ocused on epo ing se e e hypoglycaemic e en s only, and may no adequa ely e lec he equency o hypoglycaemic e en s (especially non-se e e hypoglycaemic e en s) ac oss he insulin- ea ed diabe es popula ion. In con as , he p esen s udy explo ed he equency o non-se e e hypoglycaemic e en s and se e e hypoglycaemic e en s in people wi h Type 1 diabe es and people wi h insulin- ea ed Type 2 diabe es ac oss se en Eu opean coun ies. The ecalled a es o non-se e e hypoglycaemic e en s o esponden s wi h Type 1 diabe es (1.8 pe esponden , pe week) in his s udy a e compa able wi h esul s om h ee p e iously conduc ed s udies in No he n Eu ope, which epo ed non-se e e hypoglycaemic e en a es o 1.8, 2.0 and 2.2 pe esponden , pe week [6,16,17]. Ra es o non-se e e hypoglycaemic e en s o esponden s wi h Type 2 diabe es in he cu en s udy a e highe han hose epo ed in a p ospec i e single-cen e s udy in Sco land, UK (0.4–0.7 s 0.3 pe esponden , pe week) bu his a ia ion may be a ibu able o di e ences in he geog aphical egion, Type 2 diabe es ea men egimen, and s udy sample size, o he way in which hypoglycaemic e en s had been de ined [5]. Hypo- glycaemic e en s occu ed less equen ly in esponden s wi h insulin- ea ed Type 2 diabe es compa ed wi h esponden s wi h Type 1 diabe es, and p e ious s udies sugges he equency o se e e hypoglycaemic e en s in Type 2 diabe es o be app oxima ely one- hi d o ha expe ienced by people wi h Type 1 diabe es [5,18]. The esul s epo ed in he p esen s udy o se e e hypoglycaemic e en s a e consis en wi h his end (Type 1 diabe es 0.7; Type 2 0.1–0.2) and sugges a simila a io o non-se e e hypoglycaemic e en s (Type 1 diabe es 1.8; Type 2 0.4–0.7). I should be no ed ha he equency o hypoglycaemic e en s in esponden s wi h Type 2 diabe es a ies acco ding o he ea men egimen (basal-only/long-ac ing insulin-only he apy, basal-bolus/ bo h sho - and long-ac ing insulin he apy, o ano he o m o insulin he apy); howe e , his was o be expec ed gi en he di e en insulin co e age hey p o ide [11]. O e all, noc u nal e en s ep esen ed be ween one qua e and one hi d o all non-se e e hypoglycaemic e en s. In he p esen s udy, he p opo ion o o e all non-se e e hypoglycaemic e en s occu ing a nigh was 22% ( espon- den s wi h Type 1 diabe es), 32% ( esponden s wi h Type 2 diabe es ecei ing basal-only/long–ac ing insulin-only he - apy), 22% ( esponden s wi h Type 2 diabe es ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy), and 27% ( esponden s wi h Type 2 diabe es ecei ing ano he o m o insulin he apy). Few o he s udies ha e epo ed a es o noc u nal e en s, al hough he p opo ion o noc u nal e en s would be expec ed o a y be ween insulin egimens. In he p esen s udy, we in es iga ed le els o hypoglyca- emia awa eness and epo ed 10% (Type 1 diabe es) and 6–19% (Type 2 diabe es) o esponden s o be classi ied as unawa e and 53% (Type 1 diabe es) and 43–45% (Type 2 diabe es) o ha e impai ed awa eness o hypoglycaemia (based on esponden s wi h expe ience o hypoglycaemic e en s). A compa able p opo ion o esponden s wi h Type 1 diabe es we e ound o ha e impai ed awa eness (47%) o be classi ied as unawa e (13%) in a 1-yea p ospec i e s udy ha used he alida ed ques ion, ‘Do you ecognise symp- oms when you ha e a hypo?’ [15]. Fu he mo e, a c oss- sec ional s udy in a coho o 401 people wi h Type 2 diabe es, also using his ques ion, epo ed a simila p opo - ion o esponden s wi h impai ed awa eness (46%) o ha in he cu en s udy (43–45%) [18]. The e is no consensus on how o classi y awa eness, bu ou me hod bene i s om he use o h ee ca ego ies (ins ead o wo, ‘awa e’ o ‘unawa e’, as in he Cla ke e al. [19] and Gold e al. [20] me hods), which enables iden i ica ion o he g adual loss o awa eness. In addi ion, i is he only me hod p o en o pe o m simila ly ac oss language ba ie s [21]. Some conside a ion should be gi en o he di e en esponden demog aphics wi hin he cu en s udy. Fo example, symp oms o hypoglycaemia ha e been shown o decline wi h inc easing age and he p e alence o impai ed awa eness o hypoglycaemia is epo ed o inc ease wi h du a ion o Type 1 diabe es [6]; esul s may be con ounded by hese ac o s. In addi ion, he s udy by Ak am e al. [18] epo ed impai ed awa eness o hypoglycaemia o be he mos impo an isk ac o o se e e hypoglycaemia. Resul s o he cu en s udy show ha esponden s wi h Type 1 diabe es classi ied as unawa e o as ha ing impai ed awa e- ness o hypoglycaemia epo ed signi ican ly highe a es (P<0.05) o se e e hypoglycaemic e en s han esponden s who we e always awa e. Unawa e esponden s wi h Type 1 diabe es also epo ed signi ican ly highe a es o non-se e e hypoglycaemic e en s compa ed wi h awa e esponden s (P<0.05). This could be explained by unawa e esponden s ailing o ake ac ion o p e en he onse o an e en because o an inabili y o ecognize he symp oms o low blood suga . Addi ionally, his inabili y may cause esponden s o o e - compensa e by es ing hei blood glucose mo e equen ly, esul ing in he iden i ica ion o mo e e en s; howe e , his is an a ea ha equi es u he in es iga ion, especially as hese ends we e no obse ed in esponden s wi h Type 2 diabe es. An impo an inding o he cu en s udy was he high p opo ion o esponden s wi h Type 1 diabe es (65%) and 98 ª2013 The Au ho s. Diabe ic Medicine published by John Wiley & Sons L d on behal o Diabe es UK. DIABETICMedicine Sel - epo ed non-se e e hypoglycaemic e en s in Eu ope C. G. € Os enson e al. Type 2 diabe es (50–59%) who a ely o ne e in o med hei gene al p ac i ione /specialis abou hei hypoglycae- mic e en s. Despi e hese esul s, only 17% o esponden s wi h Type 1 diabe es and 21–28% o esponden s wi h Type 2 diabe es said ha hei gene al p ac i ione /specialis did no ask hem abou hypoglycaemia du ing ou ine appoin - men s, sugges ing some le el o communica ion ega ding hypoglycaemic e en s is aking place. The eluc ance o people wi h diabe es o discuss hei hypoglycaemia may be caused by wide ac o s such as conce ns ega ding d i ing p i ileges [9], implica ions o employmen , o ea ha hey may be pe cei ed by hei gene al p ac i ione /specialis o ha e poo con ol o hei diabe es. Fu he esea ch is needed o unde s and he easoning behind why people may no ac i ely be epo ing hei hypoglycaemic e en s. Along wi h discussions on he equency o non-se e e hypoglycae- mic e en s and se e e hypoglycaemic e en s, o he impo an aspec s such as impai ed hypoglycaemia awa eness [18] and ea o hypoglycaemia [9,10] should be add essed, gi en ha hese a e associa ed wi h an inc eased isk o se e e hypoglycaemic e en s [18] and a isk o subop imum glycaemic con ol [9,10], espec i ely. An oppo uni y exis s o mo e s anda dized measu es o hese sel - epo ed ou - comes, which may also help o imp o e unde s anding o people wi h diabe es, and imp o e communica ion le els. Wi h he endo semen by bo h he Ame ican Diabe es Associa ion and he Eu opean Associa ion o he S udy o Diabe es o educa ion ega ding ecogni ion and ea men o hypoglycaemia [11], i is hoped ha communica ion be ween people wi h diabe es and hei physicians will inc ease u he . Whils g ea e educa ion could be expec ed o imp o e blood glucose managemen , he e will s ill be an unde lying inc ease in hypoglycaemic complica ions as insu- lin ea men egimens a e in ensi ied o e ime [1]. This is suppo ed by ou cu en eg ession analysis, whe e he numbe o non-se e e e en s inc eased wi h du a ion o insulin ea men . The equency o hypoglycaemic e en s epo ed du ing andomized ials, such as he Diabe es Con ol and Com- plica ions T ial [22], and he Uni ed Kingdom P ospec i e Diabe es S udy [23], may no be e lec i e o he incidence in eal-wo ld p ac ice because o ial inclusion and exclusion c i e ia and because obse a ional s udies ha e epo ed a highe incidence o hypoglycaemic e en s in unselec ed popula ions [1]. In addi ion, he e a e key bene i s o ob aining da a di ec ly om people wi h diabe es, pa icu- la ly since a high numbe o hem a e no epo ing non-se e e hypoglycaemic e en s o hei doc o . I is impo an ha he limi a ions o his s udy a e conside ed. Responden demog aphics show ha 8% o esponden s wi h Type 1 diabe es ecei e long-ac ing insulin-only he apy. I is likely ha his igu e may be he esul o inco ec epo ing o diabe es ype by esponden s wi h Type 2 diabe es. As a esul , gi en ha esponden s wi h Type 2 diabe es ha e ewe hypoglycae- mic e en s, ou s udy may unde es ima e he equency o e en s o esponden s wi h Type 1 diabe es. The su ey is based upon he ecall o bo h se e e hypoglycaemic e en s and non-se e e hypoglycaemic e en s and he in e p e a ion o symp oms is open o bias. A p e ious s udy showed ha a esponden ’s abili y o emembe non-se e e hypoglycae- mic e en s du ing he p e ious week was no signi ican ly di e en om he p ospec i e eco ding o e en s o e 1 week [6]. The cu en s udy was he e o e designed o maximize he op imum ecall pe iod, by asking esponden s o eco d e en s occu ing in he p e ious week o each o he ou ques ionnai es o e 4 consecu i e weeks. Also, a p e ious s udy has shown ha people wi h Type 1 diabe es and people wi h Type 2 diabe es a e able o accu a ely ecall se e e hypoglycaemic e en s wi hin a 1-yea pe iod (co esponding o he ecall pe iod in he cu en s udy) [15]. The e is also he po en ial ha he du a ion o he s udy may o e - o unde es ima e he annual equency o hypoglycaemia, gi en ha seasonal a ia ion was no conside ed ( he s udy was conduc ed Decembe –May). The ec ui men o esponden s, mos ly ia online panels and he equi emen o an email add ess in o de o pa icipa e in he s udy could ha e in oduced selec ion bias; howe e , he in e ne pene a ion a es o all o he coun ies s udied a e high (80–97%) [24]. The anonymous na u e o he online panel may allow a be e means o ob aining sel - epo ed da a on a eas such as communica- ion le els wi h physicians. Rec ui men was ia b oad panels e lec i e o he gene al popula ion and esponden s we e in i ed ia email o pa icipa e in he su ey by ollowing a link, and we e no in o med ha he su ey was abou hypoglycaemia be o e hey clicked on he link o en e he su ey. The e a e he e o e no easons o sugges any selec ion bias owa ds people s uggling wi h hypo- glycaemia in he i s wa e o he s udy; howe e , since he esponse a es o subsequen wa es diminished (76, 66 and 57% o esponden s comple ed wa es wo, h ee and ou , espec i ely) we canno exclude he possibili y ha la e wa es we e comple ed by esponden s who had mo e expe ience o hypoglycaemic e en s. Ne e heless, a sub- sequen analysis compa ing e en a es o he di e en wa es did no sugges any ends owa ds highe equency in la e wa es. The a ge ec ui men a e o 600 espon- den s pe coun y was no eached in Aus ia, No way and Swi ze land because o di icul ies in accessing people wi h diabe es; howe e , esul s we e ema kably consis en ac oss he coun ies. Some esponden s did no comple e all ou wa es, bu only small changes in he non-se e e hypoglycaemic e en a es (1.09 in wa e 1 o 0.93 in wa e 4) we e seen when compa ing da a ac oss wa es. This was a desc ip i e s udy, he e o e, ew compa isons we e explo ed and no adjus men s we e made o mul iple c oss-coun y compa isons; howe e , a ia ions in non-se e e hypoglycaemic e en a es ac oss coun ies we e 1.3–2.0 pe esponden , pe week in Type 1 diabe es, and ª2013 The Au ho s. Diabe ic Medicine published by John Wiley & Sons L d on behal o Diabe es UK. 99 Resea ch a icle DIABETICMedicine 0.2–1.0 pe esponden , pe week in Type 2 diabe es (0.2–0.5 in Type 2 diabe es esponden s ecei ing basa- l-only/long-ac ing insulin-only he apy, 0.5–1.0 in Type 2 diabe es esponden s ecei ing basal-bolus/bo h sho - and long-ac ing insulin he apy and 0.2–0.9 in Type 2 diabe es esponden s ecei ing ano he o m o insulin he apy). This migh e lec o he demog aphic di e ences which we e no cap u ed, such as local di e ences in ea men egimens, di e en pa ien educa ion le els o a ge s o glycaemic con ol. Addi ionally, he ec ui men me hod does no di e en ia e be ween p ima y and seconda y ca e pa ien s, which may also ha e an impac . Despi e hese limi a ions, he p esen s udy epo s he eal-wo ld a es o hypoglycaemic e en s in a la ge numbe o people wi h Type 1 diabe es and people wi h Type 2 diabe es ac oss se en Eu opean coun ies and p o ides e idence o a need o minimize he equency o hypo- glycaemia. I is acknowledged ha bo h se e e and non-se e e hypoglycaemic e en s a e mo e equen in people wi h Type 1 diabe es, bu he associa ed social and economic bu den o e en s in people wi h Type 2 diabe es is likely o be subs an ial gi en he global epidemic o Type 2 diabe es [25]. Hypoglycaemia p esen s a ba ie o op imum glycaemic con ol, inc easing he isk o diabe ic complica ions and mo ali y; he e o e, discussion du ing physician consul a ions and educa ion on he ecogni ion and ea men o hypoglycaemic e en s o people wi h diabe es a e impe a i e o encou age g ea e communica- ion wi h physicians. Funding sou ces This s udy was unded by No oNo disk. Compe ing in e es s R. Wei gasse has ecei ed hono a ia o lec u es and as a membe o he Ad iso y Boa d o No o No disk, Eli Lilly, Sano i, No a is, Med onic, MSD, Takeda, As a Zeneca/ BMS, Boeh inge -Ingelheim and Roche Diagnos ics. J. Lah ela has ecei ed hono a ia as a symposium speake o No a is, Sano i, No o No disk, MSD symposia. C. G. € Os enson has ecei ed hono a ia as a symposium speake o No o No disk Scandina ia. P. Geelhoed-Duij es ijn has ecei ed hono a ia o lec u es om No o No disk and as a membe o he Ad iso y Boa ds o Med onic, Sano i A en is and Elli Lilly. U. Pede sen-Bje gaa d has ecei ed hono a ia o lec u es and consul ancy om No o No disk, Sano i A en is, and BMS and has se ed as a membe o Ad iso y Boa d o No o No disk. M. Ma ke Jensen is employed by No o No disk Scandina ia AB. Acknowledgemen s Edi o ial suppo was p o ided by Adelphi Values. Re e ences 1 UK Hypoglycaemia S udy G oup. Risk o hypoglycaemia in ypes 1 and 2 diabe es: e ec s o ea men modali ies and hei du a ion. Diabe ologia 2007; 50: 1140–1147. 2 Eu opean Medicines Agency Commi ee o Medical P oduc s o Human Use (CHMP). Guidelines on clinical in es iga ion o medical p oduc s in he ea men o p e en ion o diabe es melli us. Eu opean Medicines Agency, 2012. A ailable a h p:// www.ema.eu opa.eu/ema/index.jsp?cu l=pages/includes/documen / documen _de ail.jsp?webCon en Id=WC500129256&mid=WC0b01 ac058009a3dc Las accessed 5 July 2013. 3 Ame ican Diabe es Associa ion Wo kg oup on Hypoglycemia. De ining and Repo ing Hypoglycemia in Diabe es. 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