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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 HbA 1c and C-peptide were measured. Hypoglycaemic episodes were defined as interstitial glucose ≤ 3.9 mmol/l (IG 3.9 ) or ≤ 3.0 mmol/l (IG 3.0 ) for ≥ 15 min, and were considered asymptomatic if no hypoglycaemic symptoms were reported., Results: At thresholds IG 3.9 and IG 3.0 , 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 IG 3.9 and IG 3.0 [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 HbA 1c 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., (© 2018 Diabetes UK.)

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 HbA 1c 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., (© 2017 Diabetes UK.)

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., (© 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.)

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 HbA(1c) 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., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

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., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

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 (> or = 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.

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.

Aims: The reported risk of severe hypoglycaemia in insulin-treated Type 2 diabetes is highly variable and few studies have evaluated the influence of risk factors. We assessed the incidence and the influence of potential risk factors for severe hypoglycaemia in a questionnaire survey in subjects with insulin-treated Type 2 diabetes receiving currently recommended multifactorial intervention., Methods: Consecutive patients with insulin-treated Type 2 diabetes (n = 401) completed a questionnaire about occurrence of hypoglycaemia in the past, hypoglycaemia awareness and socio-demographic factors. A zero-inflated negative binomial model was used to assess the influence of potential risk factors on the rate of severe hypoglycaemia., Results: The overall incidence of severe hypoglycaemia in the preceding year was 0.44 episodes/person year. Sixty-six (16.5%) patients had experienced at least one event. The risk of any episode of severe hypoglycaemia positively correlated with impaired hypoglycaemia awareness, being married and long duration of diabetes. The risk of repeated episodes of severe hypoglycaemia positively correlated with the presence of peripheral neuropathy, while long duration of diabetes prior to insulin treatment and treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists (ARBs) were associated with reduced risk. C-peptide concentration and HbA1c were not associated with the risk of severe hypoglycaemia., Conclusions: In this cohort of insulin-treated Type 2 diabetic patients, the incidence of severe hypoglycaemia is higher than reported in most studies, corresponding to about one-third of that in Type 1 diabetes. Impaired hypoglycaemia awareness is the most important risk factor for severe hypoglycaemia.

Aim: 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)., Methods: 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., Results: 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)., Conclusion: Hypoglycaemic episodes recorded by CGMS are reproducible and agreement with independent SMBG values is acceptable for retrospective recording of hypoglycaemic events with CGMS.

Aims: After Danish nationwide investigations (1987, 1989) demonstrated unacceptable blood glucose control in unselected young diabetic patients, we set out to estimate the present glycaemic control and the prevalence of microvascular complications in a cohort of children and adolescents participating in the two previous studies., Methods: This follow-up represents 339 patients (47% of the inception cohort), median age 21.1 years (range 12.0-26.9), median diabetes duration 13.2 years (range 8.9-24.5). A standardized questionnaire, fundus photographs (with central reading) and a physical examination were performed. HbA1c and overnight albumin excretion rate (AER) were analysed centrally., Results: Although 88% (n= 309) of the young persons were treated with three or more daily insulin injections, HbA1c (nondiabetic range 4.3-5.8, mean 5.3%) was 9.7+/-1.7% (mean+/-SD). Males had higher HbA1c values than females (P < 0.015). Mean daily insulin dose was 0.92+/-0.25 IU.kg(-1).24h(-1). Microalbuminuria (AER > 20-150 microg/min) and macroalbuminuria (AER > 150 microg/min) were found in 9.0% and 3.7% of the patients, respectively, and was associated with increased diastolic blood pressure (P<0.01) and presence of retinopathy (P<0.01). Retinopathy was present in approximately 60% of the patients and was associated with age, diabetes duration, HbA1c, diastolic blood pressure and AER (all P<0.01). Subclinical neuropathy (vibration perception threshold by biothesiometry > 6.5 V) was found in 62% and showed a significant association with age, linear height, diastolic blood pressure (all P < 0.01) and diabetic retinopathy (P = 0.01)., Conclusions: In spite of the majority of the patients being on multiple insulin injections, only 11% had HbA1c values below 8% and the prevalence of diabetic microvascular complications in kidneys, eyes and nerves was unacceptable high.

The frequency of symptomatic hypoglycaemic episodes was studied in 411 randomly selected conventionally treated Type 1 diabetic out-patients. Between two consecutive visits to the out-patient clinic each patient filled in a questionnaire at home. The number of hypoglycaemic episodes was then recorded prospectively in a diary for 1 week. From the questionnaires, the (retrospective) frequencies of mild and severe symptomatic hypoglycaemia were 1.6 and 0.029 episodes patient-1 week-1. From the diaries, the (prospective) frequencies of mild and severe hypoglycaemic episodes were 1.8 and 0.027 patient-1 week-1. Symptomatic hypoglycaemia was more frequent on working days than during weekends (1.8:1) and more frequent in the morning than during the afternoon, evening, and night (4.5:2.2:1.4:1). The symptoms of hypoglycaemia were non-specific, heterogeneous, and weakened with increasing duration of diabetes. During their diabetic life, 36% of the patients had experienced hypoglycaemic coma. The frequency of hypoglycaemia was positively, but only weakly, correlated with insulin dose, number of injections, percentage unmodified insulin of the total dose, and HbA1c (mild hypoglycaemia only). The frequency was also negatively, but weakly, correlated with age and HbA1c (episodes with coma only), but not correlated with sex, duration of diabetes, or patients' ratings of worries about mild and severe hypoglycaemia.

The frequency and distribution of daytime biochemical hypoglycaemia (capillary blood glucose concentration below 3 mmol/l) was assessed in type 1 diabetic patients on conventional twice daily insulin therapy (n = 79) and on continuous subcutaneous insulin infusion (n = 20). Patients collected and mailed to the hospital blood for seven-point blood glucose profiles. For both treatment regimens the frequency of biochemical hypoglycaemia on individual days was inversely related to the median blood glucose concentration in a curvilinear manner (p less than 0.001). Hypoglycaemia was more frequent pre-prandially than post-prandially (p less than 0.01), and was evenly distributed during the day in patients on continuous subcutaneous insulin infusion. In patients on conventional therapy, however, pre-lunch hypoglycaemia was four times more frequent than pre-breakfast or pre-dinner hypoglycaemia (p less than 0.0001).