hypoglycaemia is a major side effect of some glucoselowering therapies , in particular , insulin and the insulin secretagogues ( sulphonylureas and glinides ) . it is a frequent occurrence in people treated with insulin and is more common in type  1 than in type  2 diabetes 1 , 2 , 3 . hypoglycaemia increases in frequency and severity with the duration of insulin treatment 3 . impaired awareness of hypoglycaemia is common in people treated with insulin , particularly those with type  1 diabetes 4 . hypoglycaemia has a significant burden as it can engender fear and anxiety , disrupt sleep and adversely affect domestic and social life 5 , 6 . interestingly , rates of severe hypoglycaemia have not generally diminished over the years , despite the introduction of insulin analogues and advances in glucose monitoring 7 , 8 . this may be a consequence of the drive to tighter glucose targets , which have diminished the benefits of technological advances . attempting to reduce this burden can encourage the maintenance of a suboptimal glycaemic control 5 , 9 , 10 , and both the severity and frequency of hypoglycaemia unequivocally reduce healthrelated quality of life 11 , 12 , 13 , 14 . hypoglycaemia is also a burden on healthcare resources and on society as a consequence of the direct costs of its treatment and the indirect costs associated with lost productivity 9 , 15 , 16 . these and other factors can negatively influence physicians and people with diabetes , promoting reluctance to initiate or intensify therapy  insulin in particular  because of the perceived burden of hypoglycaemia 10 , 17 . the benefits of stricter glycaemic control are counterbalanced by the enhanced risk of concomitant hypoglycaemia . the most expensive aspect of treating severe hypoglycaemia is hospital admission and inpatient care 15 , 16 . severe hypoglycaemia is a common cause of hospitalization in elderly people with diabetes 18 , 19 , 20 , 21 . to our knowledge , no largescale studies of the resource use associated with severe hypoglycaemia have been performed that have examined this resource use according to type of diabetes and insulin regimen . the aim of this analysis was to estimate the resource use attributable to severe hypoglycaemia events in a large cohort of people with insulintreated diabetes , using data from a largescale clinical trial programme . this analysis used data from the insulin degludec ( ideg ) and insulin degludec / insulin aspart ( idegasp ) phase  3a clinical trial programme , including 15 phase  3a therapeutic confirmatory trials , which involved more than 8000 participants . all trials were registered on clinicaltrials.gov , the trial protocols were approved by independent ethics committees or institutional review boards , and written informed consent was obtained from participants before enrolment . trials were undertaken in accordance with the declaration of helsinki and good clinical practice guidelines 22 , 23 . the trials were categorized into three groups , depending on the patient population and the type of insulin regimen : type  1 diabetes receiving basal  bolus therapy , type  2 diabetes receiving multiple daily injections and type  2 diabetes receiving basal  oral therapy . severe hypoglycaemia events were identified using information relating to adverseevent case reports in the clinical trial safety database . only clearly stated resource use was included in the analysis , and all events were analysed independently . the data were analysed descriptively , taking into consideration three variables ( that are not necessarily mutually exclusive ) : 
 nonmedical assistance only , with the response categories : yes , no.ambulance or ( onsite ) emergency team , with the response categories : yes , no.hospital or emergency room visit , with the response categories : no , yes   24  h , yes >  24  h. 
  nonmedical assistance only , with the response categories : yes , no . ambulance or ( onsite ) emergency team , with the response categories : yes , no . hospital or emergency room visit , with the response categories : no , yes   24  h , yes >  24  h. given the multiplicity of countries in the trial programme , it was decided not to attempt to distinguish between hospital inpatient treatment and emergency room treatment ( with subsequent discharge ) , because the local procedures varied . hospital visits were therefore distinguished solely on duration (   24  h or >  24  h ) . details of the trials and characteristics of the patient populations are summarized in table  1 
 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 . in general , people with type  1 diabetes had a lower mean age , longer disease duration and lower bmi compared with those with type  2 diabetes . across the 15 openlabel , randomized , treattotarget clinical trials , severe hypoglycaemia was an infrequent occurrence : 536 severe hypoglycaemia events were recorded and analysed from a total of 8364 patient records . most occurred in people with type  1 diabetes receiving basal  bolus therapy , fewer occurred in those with type  2 diabetes on multiple daily injections , and a small number occurred in people with type  2 diabetes on basal  oral therapy ( table  1 ) . all but one event occurred in the iglar arm in the trials 3590 and 3593 . as a proportion of the number of randomized patients included in the safety analysis set in each trial . biasp 30 , biphasic insulin aspart ; bid , twice daily ; bmi , body mass index ; ideg , insulin degludec ; idegasp , insulin degludec / insulin aspart ; idet , insulin detemir ; iglar , insulin glargine . overall , 157/536 ( 29.3% ) of severe hypoglycaemia events required an ambulance / emergency team ( mainly involving paramedics , but also including physicians , although the analysis did not distinguish between them ) ( table  2 ) . additionally , following 100/536 ( 18.7% ) of the severe hypoglycaemia events , hospital or emergency room treatment was required , with 36/536 ( 6.7% points ) of these requiring a hospital stay of >  24  h ( table  2 ) . proportion of severe hypoglycaemia events leading to ambulance , emergency room or hospital visits although fewer events were recorded in people with type  2 compared with type  1 diabetes , once an event occurred , the proportion resulting in hospital or emergency room treatment was greatest in the basal  oral therapy treatment group . resources were used in relation to 57.1% , 45.3% and 37.9% of severe hypoglycaemia events in the type  2 diabetes basal  oral therapy , type  2 diabetes multiple daily injections and type  1 diabetes basal the greatest difference was in the proportion of events requiring a hospital stay of >  24  h : 47.6% in the type  2 diabetes basal oral therapy , 5.3% for type  2 diabetes multiple daily injections , and 5.0% for the type  1 diabetes basal  bolus group ( table  2 ) . the proportion of severe hypoglycaemia events utilizing medical resources . medical resource use includes use of ambulance / emergency team , hospital visit <  24  h and >  24  h. the variables measured were not necessarily mutually exclusive . poor glycaemic control in diabetes is associated with serious complications such as sightthreatening retinopathy and renal failure , and optimizing glycaemic control is fundamental to minimize this morbidity 37 , 38 , 39 . however , severe hypoglycaemia , a serious adverse effect of some glucoselowering therapies  particularly insulin  can also cause significant morbidity and have quality of life and economic consequences . this analysis utilized data from a largescale clinical trial programme and subdivided records by type of diabetes and also by insulin regimen . this has shown that in the controlled clinical trial setting , severe hypoglycaemia seldom occurs , but when it does , it leads to direct healthcare resource use in ~  40% of cases . a large difference was observed between the different regimens in the proportion of people experiencing severe hypoglycaemia who required hospitalization for >  24  h. the proportion of participants using resources following a severe hypoglycaemia event was highest in the people with type  2 diabetes on basal  oral therapy , despite the overall lower number of events compared with the patients on multiple daily injections . this may be because many of the participants receiving basal  oral therapy ( and their family / carers ) were much less experienced in treating severe hypoglycaemia . they may be more inclined to seek medical assistance , in contrast to people with type  1 diabetes and those with insulintreated type  2 diabetes taking multiple daily injections who probably have greater experience of exposure to severe hypoglycaemia . people with diabetes and their family members in these groups are less likely to seek assistance because they have learned to cope effectively with this emergency and the immediate requirements of treating an episode of severe hypoglycaemia . furthermore , the people with type  2 diabetes included in the trials had a higher mean age than those with type  1 diabetes , and this may mean that more of them had more comorbidities , were frailer and were more vulnerable to morbidity associated with severe hypoglycaemia , so contributing to the longer duration of hospital admissions . several studies have shown that hypoglycaemia requiring hospital treatment is more frequent in the elderly compared with younger people with diabetes 19 , 20 , 21 . it should also be noted that , in some trials , people with type  2 diabetes were taking concomitant oral antidiabetes agents , including sulphonylureas , and it is not clear whether these contributed to any of the severe hypoglycaemia events . some specialists believe that hospital admission is necessary for people who experience severe hypoglycaemia as a consequence of sulphonylurea therapy , which might account for some of the hospital attendances by the participants receiving basal  oral therapy 40 , 41 . a previous study observed that the proportion of people for whom emergency medical assistance was sought was higher in those with type  2 diabetes than with type  1 diabetes ( 33% vs. 10% ) 2 . a populationbased study analysing resource use associated with severe hypoglycaemia treated by emergency medical services in tayside , scotland , recorded 260 episodes over a 12month period . of these , 34% involved the ambulance service alone , 7% were treated by emergency / primary care services alone and 52% used both . some 28% of cases required hospital admission , resulting in hospital occupancy of 230 bed days 16 . although this is higher than the 18.6% who visited hospital in our study , it should be noted that this scottish study analysed only those events that had required emergency medical treatment , thus representing a more severe end of the spectrum . the use of medical resources following severe hypoglycaemia is costly , considering the large number of people with insulintreated diabetes and the extensive use of sulphonylureas . for example , an estimate of this resource utilization and associated financial burden based on the 20132014 uk national health service tariffs for  admitted patient care & outpatient procedures  diabetes with hypoglycaemic disorders equates to  1269 for people aged   69  years and  2187 for people aged   70  years , in addition to  235 for an ambulance transfer . this yields an average cost per event across treatment regimens of  305 [ ( 11.9%  + 6.7% )  *   1269  +  29.3%  *   235 ] for people aged   69 years and  476 [ ( 11.9%  +  6.7% )  *   2187  +  29.3%  *   235 ] for people aged   70  years 42 . hypoglycaemia is more costly in elderly populations with diabetes , who may be much more susceptible to severe hypoglycaemia , perhaps in relation to coexisting comorbidities 18 , 19 , 20 , 21 . several other studies using different methodologies have provided results that are in broad agreement with our study . hospitalization is the major cost associated with treating hypoglycaemia , but costs vary depending on the countries involved and local practices and procedures . for example , the costs associated with treating hypoglycaemia in germany are higher than elsewhere because people with diabetes are often admitted to hospital for several days to receive additional education 43 . the study based in tayside estimated the direct  costs of treating severe hypoglycaemia  based on  127 for an ambulance ,  89 for emergency room treatment and  218 for each patient admitted to a ward  to be over  13 million per year for the uk in 2003 ( equivalent to  17  million in 2014 prices ) 16 . based on these values , the cost of a single severe hypoglycaemia event , which required some medical assistance , has been estimated at  335 44 . data  obtained using a questionnaire regarding a participant 's most recent severe hypoglycaemia event performed in germany , spain and the uk revealed that the cost of treating a person with type  2 diabetes ( germany ,  533 ; spain ,  691 ; uk ,  537 ) was higher than for a person with type  1 diabetes (  441 ,  577 and  236 , respectively ) 15 . a usbased study investigating the cost of hypoglycaemia in people with insulintreated type  2 diabetes estimated the direct costs of severe events requiring assistance from a healthcare professional as $ 1729 , whereas those events requiring nonmedical assistance were $ 242 per event 45 . most previous studies have been retrospective assessments of all people with severe hypoglycaemia , and often exclusively those who had utilized additional healthcare resources . although some of these studies included cost analyses , they did not include all severe hypoglycaemia events , so it is difficult to determine what proportion of events required ambulance and hospital treatment . this study benefits from its size and the more accurate and reliable recording associated with controlled clinical trials , by contrast with data that have been collected in realworld observational or retrospective studies . this study has the limitation that the rates of hypoglycaemia may be lower than in a realworld setting , because people at high risk of severe hypoglycaemia or who were judged by the investigator to have impaired hypoglycaemia awareness were excluded from the clinical trials . however , because the examination was not primarily aimed at assessing the risk of events , but rather exploring the consequences of such an event , it is unclear to what extent such a limitation would influence the results . additionally , because of the global nature of the clinical trials , a huge variation in healthcare utilization and local procedures are to be expected , making estimates of resource use difficult to determine with accuracy . healthcare utilization in trials is often protocol driven , but this has not been assumed in this analysis because of the acute nature of severe hypoglycaemia . potential exists for the underreporting of ambulance use , or inconsistent reporting of resource use . although it is known when people had attended hospital , information about how they arrived there was not consistently recorded , so only clearly stated resource use was included in the analysis . this study did not attempt to capture length of stay or what medication was received because this would be healthcaresector specific and could be confounded by other comorbidities . the study has reported only the direct resource use relating to the involvement of emergency services and hospital treatment and does not include additional blood glucose measurements , costs of glucagon or intravenous dextrose , or any subsequent medical consultations that were necessary following a severe hypoglycaemia episode . this analysis suggests that severe hypoglycaemia events often result in emergency / ambulance calls and treatment in hospital , thereby incurring a substantial economic burden . a high rate of resource utilization was observed with all insulin regimens , and although the incidence of severe hypoglycaemia events was low , the greatest level of resource use following an event occurred in people with type  2 diabetes on a regimen of basal insulin combined with oral antidiabetes drugs . novo nordisk contributed to the study design and conduct , data collection , analysis and interpretation of the trials . sh has served on advisory panels and speaker bureaus for eli lilly , novo nordisk and takeda , and received research support from medtronic . bmf has served on advisory panels and speaker bureaus for eli lilly , novo nordisk , msd , sanofi , boehringer ingelheim and janssen . sg has served on advisory boards for novo nordisk , sanofi , takeda and eli lilly and has received research support from novo nordisk , sanofi and takeda . all authors contributed to the design , interpretation , writing , evaluation and approval of this manuscript .