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Aim: The epidemiology of asymptomatic (silent) hypoglycaemia is not well‐described. We investigated incidence and risk factors for asymptomatic hypoglycaemia in Type 1 diabetes. Methods: A cohort of 153 people with Type 1 diabetes participated in 6 days of blinded continuous glucose monitoring (CGM) and recording of hypoglycaemia symptoms. At entry, hypoglycaemia awareness was classified (by three different methods) and HbA1c and C‐peptide were measured. Hypoglycaemic episodes were defined as interstitial glucose ≤ 3.9 mmol/l (IG3.9) or ≤ 3.0 mmol/l (IG3.0) for ≥ 15 min, and were considered asymptomatic if no hypoglycaemic symptoms were reported. Results: At thresholds IG3.9 and IG3.0, the incidence rates of hypoglycaemic episodes were 5.0 (7.9) [median (IQR)] and 1.3 (3.4) episodes/person‐week, respectively. Three‐quarters of episodes were asymptomatic. In total, 77% and 52% of participants experienced one or more episode of asymptomatic hypoglycaemia at IG3.9 and IG3.0 [3.0 (6.2) and 1.0 (2.3) asymptomatic episodes/person‐week]. At multivariate analysis, reduced awareness was positively associated with asymptomatic hypoglycaemia, particularly nocturnal events, and negatively with symptomatic hypoglycaemia. High insulin dose was associated with increased risk of both asymptomatic and symptomatic hypoglycaemia, whereas low HbA1c and long diabetes duration were risk factors only for symptomatic hypoglycaemia. Conclusions: Asymptomatic hypoglycaemia constitutes the majority of hypoglycaemic events in Type 1 diabetes. Reduced hypoglycaemia awareness and high insulin dose are risk factors for asymptomatic hypoglycaemia but other conventional risk factors for severe hypoglycaemia do not correlate with risk of asymptomatic episodes. What's new?: The existence of asymptomatic hypoglycaemia in Type 1 diabetes has been described previously but the epidemiology of these episodes has not been explored, thus rates of asymptomatic hypoglycaemia are unclear.This study reveals that asymptomatic hypoglycaemia constitutes the majority of hypoglycaemic episodes in Type 1 diabetes assessed by blinded CGM.Highlighting that self‐reported symptomatic hypoglycaemia comprises only a minor fraction of the total burden of hypoglycaemia in Type 1 diabetes; particularly, in individuals with impaired hypoglycaemia awareness.This study highlights the importance of the use of CGM in detecting asymptomatic episodes; particularly in individuals with impaired hypoglycaemia awareness. [ABSTRACT FROM AUTHOR]

Aims To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. Methods A total of 72 people [46 men, mean ± sd age 54 ± 12 years, mean ± sd HbA1c 65 ± 12 mmol/mol (8.1 ± 1.1%), mean ± sd duration of diabetes 30 ± 14 years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose ≤ 3.9 mmol/l). Results During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; P < 0.0001) with insulin analogue. Conclusions Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia. [ABSTRACT FROM AUTHOR]

Aim Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night. Methods This 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal–bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996 ). Results Analogue-based treatment resulted in a 6% (2–10%; P = 0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32–46%; P < 0.0001) reduction of non-severe nocturnal hypoglycaemia, seen for both symptomatic (48% [36–57%]; P < 0.0001) and asymptomatic (28% [14–39%]; P = 0.0004) nocturnal hypoglycaemia episodes. No clinically significant differences in hypoglycaemia occurrence were observed between the insulin regimens during the day. The time needed to treat one patient with insulin analogues to avoid one episode (TNT1) of non-severe nocturnal hypoglycaemia was approximately 3 months. Conclusion In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin. [ABSTRACT FROM AUTHOR]

Aims To examine whether severe hypoglycaemia and impaired hypoglycaemic awareness, a principal predictor of severe hypoglycaemia, are associated with all-cause mortality or cardiovascular mortality in Type 1 diabetes mellitus. Methods Mortality was recorded in two cohorts, one in Denmark (n = 269, follow-up 12 years) and one in the Netherlands (n = 482, follow-up 6.5 years). In both cohorts, awareness class was characterized and numbers of episodes of severe hypoglycaemia either during lifetime (Danish cohort) or during the preceding year (Dutch cohort) were recorded. In addition, episodes of severe hypoglycaemia were prospectively recorded every month for 1 year in the Danish cohort. Follow-up data regarding mortality were obtained through medical reports and registries (Danish cohort). Results All-cause mortality was 14% (n = 39) in the Danish and 4% (n = 20) in the Dutch cohort. In either cohort, neither presence of episodes with severe hypoglycaemia nor impaired hypoglycaemia awareness were associated with increased mortality in age-truncated Cox proportional hazard regression models. Variables associated with increased risk of all-cause mortality in both cohorts were evidence of macrovascular disease and reduced kidney function. Conclusions Severe hypoglycaemia and hypoglycaemia unawareness are not associated with increased risk of all-cause or cardiovascular mortality in people with Type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Diabet. Med. 29, 558-566 (2012) Abstract Aims To explore incidence, risk factors, possible pathophysiological factors and clinical management of hypoglycaemia during pregnancy in women with Type 1 diabetes. Methods Literature review. Results In women with Type 1 diabetes, severe hypoglycaemia occurs three to five times more frequently in early pregnancy than in the period prior to pregnancy, whereas in the third trimester the incidence of severe hypoglycaemia is lower than in the year preceding pregnancy. The frequency distribution of severe hypoglycaemia is much skewed, as 10% of the pregnant women account for 60% of all recorded events. Risk factors for severe hypoglycaemia during pregnancy include a history with severe hypoglycaemia in the year preceding pregnancy, impaired hypoglycaemia awareness, long duration of diabetes, low HbA1c in early pregnancy, fluctuating plasma glucose values (≤ 3.9 mmol/l or ≥ 10.0 mmol/l) and excessive use of supplementary insulin injections between meals. Pregnancy-induced nausea and vomiting seem not to be contributing factors. Conclusions Striving for near-normoglycaemia with focus on reduction of plasma glucose fluctuations during pregnancy should have high priority among clinicians with the persistent aim of improving pregnancy outcome among women with Type 1 diabetes. Pre-conception counselling, carbohydrate counting, use of insulin analogues, continuous subcutaneous insulin infusion (insulin pump) therapy and real-time continuous glucose monitoring with alarms for low glucose values might be relevant tools to obtain near-normoglycaemia without episodes of severe hypoglycaemia. [ABSTRACT FROM AUTHOR]

Diabet. Med. 29, 303-312 (2012) Abstract Aims To estimate short-term cost-effectiveness of insulin detemir vs. NPH insulin based on the incidence of mild hypoglycaemia in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands. Methods A model was developed to evaluate cost-effectiveness based on mild (self-treated) hypoglycaemia and pharmacy costs over 1 year. Published rates of mild hypoglycaemia were used for NPH insulin and insulin detemir. Effectiveness was calculated in terms of quality-adjusted life expectancy. Pharmacy costs were accounted using published prices and defined daily doses for both insulins. Costs were expressed in 2010 euros (€). Results Treatment with insulin detemir was associated with fewer mild hypoglycaemic events than NPH insulin (mean rates of 26.3 vs. 35.5 events per person-year), leading to an improvement in mean quality-adjusted life expectancy of approximately 0.019 (0.030) quality-adjusted life years (standard deviation). Annual costs were € 573.55 (110.42) vs. € 332.76 (62.18) in Denmark for insulin detemir and NPH insulin, respectively. These values were € 545.79 (106.54) vs. € 306.12 (57.78) in Sweden, € 720.10 (140.74) vs. € 408.73 (78.61) in Finland and € 584.01 (109.47) vs. € 359.60 (64.84) in the Netherlands. Incremental cost-effectiveness ratios were approximately € 12 644 (Denmark), € 12 612 (Sweden), € 16 568 (Finland) and € 12 216 (the Netherlands) per quality-adjusted life year gained for insulin detemir vs. NPH insulin. Conclusions Insulin detemir is likely to be cost-effective vs. NPH insulin in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands. Increased pharmacy costs with insulin detemir should not be a barrier to therapy based on these findings. [ABSTRACT FROM AUTHOR]

Aims Severe hypoglycaemia is a significant problem in pregnant women with Type 1 diabetes. We explored whether frequent severe hypoglycaemia during pregnancy in women with Type 1 diabetes is related to placental growth hormone (GH) and insulin-like growth factor I (IGF-I) levels. Methods A prospective, observational study of 107 consecutive pregnant women with Type 1 diabetes. Blood samples were drawn for IGF-I and placental GH analyses at 8, 14, 21, 27 and 33 weeks. Severe hypoglycaemic events were reported within 24 h. Results Eleven women (10%) experienced frequent severe hypoglycaemia (≥ 5 events), accounting for 60% of all events. Throughout pregnancy, IGF-I levels were 25% lower in these women ( P < 0.005) compared with the remaining women, despite similar placental GH levels. Eighty per cent of the severe hypoglycaemic events occurred before 20 weeks when IGF-I levels were at their lowest. This finding was not explained by differences in insulin dose, median plasma glucose levels or glycated haemoglobin. History of severe hypoglycaemia the year preceding pregnancy and impaired hypoglycaemia awareness—being the only predictors of frequent severe hypoglycaemia in a logistic regression analysis—were not associated with IGF-I or placental GH levels at 8 weeks. Conclusions In women with Type 1 diabetes experiencing frequent severe hypoglycaemia during pregnancy, IGF-I levels are significantly lower compared with the remaining women despite similar placental GH levels. IGF-I levels are lowest in early pregnancy where the incidence of severe hypoglycaemia is highest. IGF-I may be a novel factor of interest in the investigation of severe hypoglycaemia in patients with Type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background: Diabetes-related anxiety influences the quality-of-life of people with diabetes. Aim: To compare diabetes-related concerns in insulin-treated patients with type 1 and type 2 diabetes. Method: A cross-sectional questionnaire survey was carried out in two cohorts of adult outpatients with type 1 diabetes (n = 223) and insulin-treated type 2 diabetes (n = 104). Assessment of concerns about mild and severe hypoglycaemia, blindness and kidney failure was carried out using the seven-point Likert scale. Results: Insulin-treated patients with type 1 or 2 diabetes worry mostly about late diabetic complications, less about severe hypoglycaemia and little about mild hypoglycaemia. Patients with type 1 diabetes worry more about severe hypoglycaemia than those with type 2 diabetes; no differences in levels of anxiety about mild hypoglycaemia, blindness and kidney failure exist. Severe hypoglycaemia in the preceding year is associated with more worry about severe hypoglycaemia in patients with type 1 or 2 diabetes. Those with type 1 or 2 diabetes who have impaired awareness of hypoglycaemia tend to worry more about severe hypoglycaemia than those with normal awareness of hypoglycaemia. The presence of eye or kidney complications does not influence the level of anxiety in people with type 1 diabetes. Patients with type 2 diabetes without complications tend to worry more about mild and severe hypoglycaemia than those with complications. Conclusion: Patients with insulin-treated diabetes worry considerably about microvascular complications and severe hypoglycaemia risk. Recent experience of severe hypoglycaemia and presence of impaired hypoglycaemia awareness are associated with increased worry scores for severe hypoglycaemia in patients with type 1 or 2 diabetes. Screening for diabetes-related concerns should be integrated into diabetes care. Copyright © 2007 FEND [ABSTRACT FROM AUTHOR]

Aim: To compare self-treatment of mild symptomatic hypoglycaemia in people with type 1 diabetes with national Danish guidelines recommending 10–20 g of refined carbohydrate initially followed by unrefined carbohydrates. Methods: A cohort of 201 patients with type 1 diabetes filled in a questionnaire including self-treatment of mild symptomatic hypoglycaemia and occurrence of mild and severe hypoglycaemia. Initial intake of less than 10 g of refined carbohydrate was defined as under treatment and intake of 20 g or more as over treatment. Results: A total of 147 patients (73%) answered both questions about initial and follow-up self-treatment of hypoglycaemia. Fifty per cent of patients treated themselves with 10–20 g refined carbohydrates (female:male = 59%:43%; p<0.05), whereas 37% over treated (female:male = 34%:39%; not significant) and 13% under treated (female:male = 6%:18%; p<0.05). Initial treatment was followed by consumption of unrefined carbohydrates in 70% of the patients. Overall, 37% (female:male = 49%:28%; p<0.05) of the patients adhered to guidelines. The number of severe hypoglycaemic episodes (lifetime) and amount of carbohydrate intake were positively correlated (r = 0.2; p<0.05). Adherence to guidelines was not related to occurrence of mild and severe (in the last year) hypoglycaemia, glycated haemoglobin, or fear of hypoglycaemia. Conclusions: Only about one-third of patients with type 1 diabetes treat mild hypoglycaemia according to guidelines. Female patients show better compliance. Patients with frequent episodes of severe hypoglycaemia over treat more often. Copyright © 2007 FEND. [ABSTRACT FROM AUTHOR]

Background: Appropriate self-treatment of mild symptomatic hypoglycaemia is essential to prevent severe hypoglycaemia. Danish national guidelines recommend 10–20 g of refined carbohydrate (CH) initially, followed by a non-specified amount of unrefined CH. Aim: Our aim was to explore the effect of the amount of CH taken on glucose concentrations recorded by the MiniMed Continuous Glucose Monitoring System (CGMS) at mild symptomatic hypoglycaemic episodes. Method: A total of 125 adult patients with type 1 diabetes underwent 6 days of CGMS. HemoCue blood glucose determinations were used for calibration. All mild symptomatic episodes with a concomitant CGMS value ≤ 3.5 mmol/l were included in the analysis. Participants completed a detailed diary documenting all meals and snacks, insulin doses, and episodes and self-treatment of hypoglycaemia. CGMS values recorded 30 and 60 minutes after the episode were compared to CH intake. An initial intake of <10 g CH was defined as under treatment, and an intake of >20 g CH as over treatment. Treatment target was CGMS values of 3.6–10.0 mmol/l; values ≤ 3.5 mmol/l were defined as insufficient treatment, and values >10.0 mmol/l as overshooting the target. Results: A total of 126 mild symptomatic episodes was experienced in 52 (42%) of the patients. Initial carbohydrate intake could be calculated for 93 episodes. At 30 minutes, under treatment was associated with increased risk of insufficient response (57% versus 30%; p<0.01). At 60 minutes, over treatment was associated with increased risk of overshooting the target (23% versus 7%; p<0.05). An independent effect of follow-up intake of unrefined CH is not detectable within the first 60 minutes after treatment. Conclusion: Current guidelines for treatment of mild symptomatic hypoglycaemia are appropriate to ensure achievement of the glycaemic target. Copyright © 2006 FEND. [ABSTRACT FROM AUTHOR]

Continuous glucose monitoring may reveal episodes of unrecognized hypoglycaemia. We evaluated reproducibility and reliability of hypoglycaemic episodes recorded in daily life by the Medtronic MiniMed Continuous Glucose Monitoring System (CGMS). Twenty-nine adult patients with Type 1 diabetes underwent 6 days of continuous subcutaneous glucose monitoring, applying one CGMS on each side of the abdomen. Blood glucose was measured by HemoCue B-Glucose Analyzers six times daily and two different 4-point calibration sets were generated (set A and B). Using these calibration sets, CGMS raw data were recalibrated generating four different CGMS data sets [left-A (left side of abdomen, calibration set A), left-B, right-A and right-B]. Agreement between CGMS data sets was evaluated during hypoglycaemic events, comparing CGMS readings = 2.2 mmol/l with nadir values from corresponding CGMS data sets. CGMS readings were also compared with independent self-monitored blood glucose (SMBG) values. With hypoglycaemia (CGMS readings = 2.2 mmol/l) in calibration set left-A, values below 3.5 mmol/l were present in 99% (95% CI: 95–100%) of samples in left-B, 91% (95% CI: 84–96%) of samples in right-A, and 90% (95% CI: 83–95%) of samples in right B. In 84% of these episodes (95% CI: 59–96%) independent SMBG values were below 3.5 mmol/l. Difference in duration was observed with a median difference of 20 min; (left-A vs. right-B). Hypoglycaemic episodes recorded by CGMS are reproducible and agreement with independent SMBG values is acceptable for retrospective recording of hypoglycaemic events with CGMS. Diabet. Med. 22, 858 –862 (2005) [ABSTRACT FROM AUTHOR]

Aims/hypothesis. We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACE gene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively. Methods. We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists. Results. There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACE gene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia. Conclusion. High ACE activity and the presence of the D allele of the ACE gene predict a high rate of severe hypoglycaemia in Type 1 diabetes. [ABSTRACT FROM AUTHOR]

The article presents a study on ACTH stimulation test in patients with type 1 diabetes and recurrent severe hypoglycaemia. The study shows that undiagnosed adrenocortical insufficiency is a rare cause of recurrent severe hypoglycaemia in patients with type 1 diabetes that rather seems to be explained by reduced hypoglycaemia awareness and other known or unknown risk indicators. Screening with an ACTH test in patients with recurrent severe hypoglycaemia is addressed.

Background Varenicline is a new drug indicated for smoking cessation. It has primarily been investigated in healthy adults. The commonest side-effects are nausea, headache, sleep disturbance, constipation, flatulence and vomiting. Hypoglycaemia has not been reported. As smoking cessation is important to reduce risk of cardiovascular morbidity, especially in diabetes, use of effective drugs indicated for smoking cessation is rational. Case report We report multiple episodes of severe hypoglycaemia after starting varenicline in a 53-year-old woman with Type 1 diabetes. Since onset of diabetes at age 25 years and until start of varenicline therapy, she had only experienced one episode of severe hypoglycaemia and hypoglycaemia awareness was not impaired. The severe hypoglycaemic episodes disappeared after withdrawal of varenicline. Conclusions We recommend cautious prescription of varenicline, intensified blood glucose monitoring and careful education of patients with diabetes treated with varenicline. Further investigation of the use of varenicline in patients with diabetes is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To investigate whether increased risk of severe hypoglycaemia in early pregnancy is related to pregnancy-induced changes in renin–angiotensin system (RAS) activity in women with type 1 diabetes (T1DM). Methods: Severe hypoglycaemic events the year preceding pregnancy were recorded retrospectively in 107 consecutive pregnant women with T1DM. Events during pregnancy were recorded prospectively. Measurements of ACE, renin and angiotensinogen were determined at 8, 14, 21, 27 and 33 weeks and postpartum. Results: The rate of severe hypoglycaemia was 1.1 and 5.3 events/patient-year the year preceding pregnancy and in first trimester, respectively (p <0.0001). Levels of ACE, renin or angiotensinogen did not differ between women with and without severe hypoglycaemia during pregnancy. Multivariate regression analysis identified a positive association between rate of severe hypoglycaemia the year preceding pregnancy and postpartum ACE activity (relative rate of severe hypoglycaemia above versus below median ACE activity: 4.4 (CI: 1.7–11.9), p =0.003). No association was found between severe hypoglycaemia during pregnancy and renin angiotensin system activity at 8 weeks. Conclusions: In early pregnancy increased RAS activity does not explain the 5-fold increase in severe hypoglycaemia in women with T1DM. A positive association between occurrence of severe hypoglycaemia and ACE activity outside pregnancy was demonstrated. [Copyright &y& Elsevier]

Abstract: Aims: To investigate whether the incidence of severe hypoglycaemia in pregnant women with type 1 diabetes can be reduced without deteriorating HbA1c levels or pregnancy outcomes in a routine care setting. Methods: Two cohorts (2004–2006; n =108 and 2009–2011; n =104) were compared. In between the cohorts a focused intervention including education of caregivers and patients in preventing hypoglycaemia was implemented. Women were included at median 8 (range 5–13) weeks. Severe hypoglycaemia (requiring assistance from others) was prospectively reported in structured interviews. Results: In the first vs. second cohort, severe hypoglycaemia during pregnancy occurred in 45% vs. 23%, p =0.0006, corresponding to incidences of 2.5 vs. 1.6 events/patient-year, p =0.04. Unconsciousness and/or convulsions occurred at 24% vs. 8% of events. Glucagon and/or glucose injections were given at 15% vs. 5% of events. At inclusion HbA1c was comparable between the cohorts while in the second cohort fewer women reported impaired hypoglycaemia awareness (56% vs. 36%, p =0.0006), insulin dose in women on multiple daily injections was lower (0.77IU/kg (0.4–1.7) vs. 0.65 (0.2–1.4), p =0.0006) and more women were on insulin analogues (rapid-acting 44% vs. 97%, p <0.0001; long-acting 6% vs. 76%, p <0.0001) and insulin pumps (5% vs. 23%, p <0.0001). Pregnancy outcomes were similar in the two cohorts. Conclusions: A 36% reduction in the incidence of severe hypoglycaemia in pregnancy with unchanged HbA1c levels and pregnancy outcomes was observed after implementation of focused intervention against severe hypoglycaemia in a routine care setting. Improved insulin treatment, increased health professional education and fewer women with impaired hypoglycaemia awareness may contribute. [Copyright &y& Elsevier]

Abstract: Introduction: The effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed regimens. Methods: A questionnaire was posted from six Danish diabetes clinics to 6112 unselected patients with type 1 diabetes and filled in by 3861 patients (63.2%). Primary endpoint was number of episodes of severe hypoglycaemia in the preceding year. Mild hypoglycaemia was also reported. Results: The frequency of severe hypoglycaemic episodes per patient-year in patients receiving long-acting insulin analogues was 1.47±0.18 versus 1.09±0.10 in patients on long-acting human insulin (p =0.01). The frequency of severe hypoglycaemic episodes per patient-year was 1.09±0.11 in patients on short-acting insulin analogues versus 1.26±0.13 in patients on short-acting human insulin (p =0.15), which was statistically significant in an adjusted analysis. Conclusions: Severe hypoglycaemia is more frequent in patients with type 1 diabetes treated with long-acting insulin analogues. Confounding by indication may be involved. Clinical intervention trials using insulin analogues in patients prone to severe hypoglycaemia are highly needed. [Copyright &y& Elsevier]