Regional variations in definitions and rates of hypoglycaemia: findings from the global HAT observational study of 27 585 people with Type 1 and insulin-treated Type 2 diabetes mellitus.

AIM: To determine participant knowledge and reporting of hypoglycaemia in the non-interventional Hypoglycaemia Assessment Tool (HAT) study. METHODS: HAT was conducted in 24 countries over a 6-month retrospective/4-week prospective period in 27 585 adults with Type 1 or insulin-treated Type 2 diabetes mellitus. Participants recorded whether hypoglycaemia was based on blood glucose levels, symptoms or both. RESULTS: Hypoglycaemia rates were consistently higher in the prospective compared with the retrospective period. Most respondents (96.8% Type 1 diabetes; 85.6% Type 2 diabetes) knew the American Diabetes Association/European Association for the Study of Diabetes hypoglycaemia definition, but there were regional differences in the use of blood glucose measurements and/or symptoms to define events. Confirmed symptomatic hypoglycaemia rates were highest in Northern Europe/Canada for Type 1 diabetes (63.9 events/year) and in Eastern Europe for Type 2 diabetes (19.4 events/year), and lowest in South East Asia (Type 1 diabetes: 6.0 events/year; Type 2 diabetes: 3.2 events/year). Unconfirmed symptomatic hypoglycaemia rates were highest in Eastern Europe for Type 1 diabetes (5.6 events/year) and South East Asia for Type 2 diabetes (4.7 events/year), and lowest for both in Russia (Type 1 diabetes: 2.1 events/year; Type 2 diabetes: 0.4 events/year). Participants in Latin America reported the highest rates of severe hypoglycaemia (Type 1 diabetes: 10.8 events/year; Type 2 diabetes 3.7 events/year) and severe hypoglycaemia requiring hospitalization (Type 1 diabetes: 0.56 events/year; Type 2 diabetes: 0.44 events/year). The lowest rates of severe hypoglycaemia were reported in South East Asia (Type 1 diabetes: 2.0 events/year) and Northern Europe/Canada (Type 2 diabetes: 1.3 events/year), and the lowest rates of severe hypoglycaemia requiring hospitalization were in Russia (Type 1 diabetes: 0.15 events/year; Type 2 diabetes: 0.09 events/year). The blood glucose cut-off used to define hypoglycaemia varied between regions (Type 1 diabetes: 3.1-3.6 mmol/l; Type 2 diabetes: 3.5-3.8 mmol/l). CONCLUSIONS: Under-reporting of hypoglycaemia rates in retrospective recall and regional variations in participant definitions of hypoglycaemia may contribute to the global differences in reported rates. Discrepancies between participant definitions and guidelines may highlight a need to redefine hypoglycaemia criteria. (Clinical Trials Registry No: NCT01696266).

Rates and predictors of hypoglycaemia in 27 585 people from 24 countries with insulin-treated type 1 and type 2 diabetes: the global HAT study.

AIMS: To determine the global extent of hypoglycaemia experienced by patients with diabetes using insulin, as there is a lack of data on the prevalence of hypoglycaemia in developed and developing countries. METHODS: This non-interventional, multicentre, 6-month retrospective and 4-week prospective study using self-assessment questionnaire and patient diaries included 27 585 patients, aged ≥18 years, with type 1 diabetes (T1D; n = 8022) or type 2 diabetes (T2D; n = 19 563) treated with insulin for >12 months, at 2004 sites in 24 countries worldwide. The primary endpoint was the proportion of patients experiencing at least one hypoglycaemic event during the observational period. RESULTS: During the prospective period, 83.0% of patients with T1D and 46.5% of patients with T2D reported hypoglycaemia. Rates of any, nocturnal and severe hypoglycaemia were 73.3 [95% confidence interval (CI) 72.6-74.0], 11.3 (95% CI 11.0-11.6) and 4.9 (95% CI 4.7-5.1) events/patient-year for T1D and 19.3 (95% CI 19.1-19.6), 3.7 (95% CI 3.6-3.8) and 2.5 events/patient-year (95% CI 2.4-2.5) for T2D, respectively. The highest rates of any hypoglycaemia were observed in Latin America for T1D and Russia for T2D. Glycated haemoglobin level was not a significant predictor of hypoglycaemia. CONCLUSIONS: We report hypoglycaemia rates in a global population, including those in countries without previous data. Overall hypoglycaemia rates were high, with large variations between geographical regions. Further investigation into these differences may help to optimize therapy and reduce the risk of hypoglycaemia.

A prospective, claims-based assessment of the risk of pancreatitis and pancreatic cancer with liraglutide compared to other antidiabetic drugs.

AIM: We evaluated the relationship between liraglutide and acute pancreatitis or pancreatic cancer in an ongoing post-marketing safety assessment programme. METHODS: Initiators of liraglutide, exenatide, metformin, pioglitazone or groups containing initiators of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US commercial health insurance claims database (1 February 2010 to 31 March 2013) and followed for a median of 15 months. We estimated incidence rates (IR/100 000 person-years), rate ratio (RR) and 95% confidence intervals (CI) of new insurance claims with diagnoses of primary inpatient acute pancreatitis or pancreatic cancer from Poisson regression models. RESULTS: The IR for acute pancreatitis for liraglutide was 187.5 compared with 154.4 for all non-glucagon-like peptide-1 (GLP-1)-based therapies (adjusted RR 1.10; CI 0.81-1.49). The IR for pancreatic cancer was 19.9 for liraglutide compared with 33.0 for all non-GLP-1-based therapies (adjusted RR 0.65; 95% CI 0.26-1.60). CONCLUSION: We did not observe excess risk of either outcome associated with liraglutide relative to individual or pooled comparator drugs.

PREDICTIVE- a global, prospective observational study to evaluate insulin detemir treatment in types 1 and 2 diabetes: baseline characteristics and predictors of hypoglycaemia from the European cohort.

AIM: PREDICTIVEtrade mark (Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation) is a large, multi-national, observational study assessing the safety and efficacy of insulin detemir. We report the study design, population characteristics and baseline observations, including cross-sectional analysis, from 19 911 patients with type 1 or 2 diabetes. METHODS: Patients with type 1 or 2 diabetes requiring basal insulin are prescribed insulin detemir and followed up for 12-52 weeks. Data on demographics, haemoglobin A(1c) (HbA(1c)), fasting glucose, within-subject fasting glucose variability and weight are collected from patient records (and/or recall for hypoglycaemia). A negative binomial distribution model is used to assess the influence of predictive/confounding variables on hypoglycaemic episodes in insulin-treated patients at baseline. Multi-factorial analysis of covariance is used to evaluate the association of the variables with current body weight and within-subject fasting glucose variability. RESULTS: Total hypoglycaemic episodes in the 4 weeks prior to study start were 47.5 per patient-year in patients with type 1 and 9.2 per patient-year in patients with type 2 diabetes. The frequency of hypoglycaemia in insulin-treated patients showed a significant, positive association with duration of diabetes, number of insulin injections and fasting glucose variability but was inversely related to HbA(1c), fasting glucose and body mass index. Weight showed a significant positive association with gender (male > female) and insulin dosage. Weight was also positively associated with fasting glucose variability in patients with type 1 diabetes, and age and number of injections in patients with type 2 diabetes. CONCLUSIONS: These baseline data showed that, in addition to the established relationship with intensive treatment and HbA(1c), frequency of hypoglycaemia was positively associated with fasting glucose variability. Follow-up data from PREDICTIVE will provide insights on insulin detemir in diabetes management.

Is the timing of withdrawal bleeding a guide to endometrial safety during sequential oestrogen-progestagen replacement therapy? UK Continuous Combined HRT Study Investigators.

Current regimens of sequential hormone replacement therapy are based on data that show a protective effect on the endometrium of at least 10 days of progestagen. In clinical practice, onset of bleeding on or after day 11 of the progestagen phase is taken as reassurance of a normal endometrium. 413 postmenopausal women taking oestrogen-progestagen hormone replacement therapy with 10 or 12 days of progestagen per cycle completed bleeding diaries for 3 months before endometrial biopsy. For most women, bleeding started around the 13th day after starting progestagen. There was no correlation between endometrial histology and timing of onset of bleeding. 11 (2.7%) women had complex endometrial hyperplasia. The prevalence of hyperplasia was 2.4% with 10 days of progestagen per cycle and 2.8% with 12 days [corrected]. The timing of onset of withdrawal bleeding during oestrogen-progestagen HRT does not predict endometrial hyperplasia.

A two-year double-blind controlled study of the clinical effect of combined and sequential postmenopausal replacement therapy and steroid metabolism during treatment.

A total of 151 postmenopausal women were randomly allocated to 3 groups for treatment with hormone replacement therapy. One group received combined therapy (2 mg oestradiol (E2) and 1 mg norethisterone acetate (NETA) daily), the second group was placed on sequential therapy (2 mg E2 for 12 days, 2 mgE2 and 1 mg NETA for 10 days and 1 mg E2 for 6 days), while the third was given placebo. Treatment was administered over 24 cycles of 28 days. The two active treatments were equally effective in relieving climacteric symptoms. In the combined therapy group, 62% of the women experienced spotting and/or breakthrough bleeding during the first 3 cycles; thereafter this proportion decreased to between 3 and 18% in each of the following three-cycle periods. Sixty-four percent (64%) of these women had no more bleeding after the first 3 cycles. Endometrial atrophy was detected in 93% of the women in this group after 24 cycles of therapy. Bleeding irregularities occurred during the first 3 cycles in 27% of the patients treated with sequential therapy and in 21% of those receiving placebo. In the subsequent 3-cycle periods these figures fell to below 10% in the 2 groups. In all 3 groups weight remained stable but blood pressure increased equally in the actively treated groups and the placebo group. The levels of follicle-stimulating hormone (FSH), sex-hormone-binding globulin (SHBG) and the free fraction of E2 in serum were significantly lower in the combined therapy group than in the sequential therapy group. The higher level of free E2 in the latter group may have been caused by a decrease in metabolism associated with the increased SHBG concentration. It was concluded that combined treatment with E2 and NETA might provide an alternative to sequential treatment in postmenopausal women willing to tolerate the initial high risk of breakthrough bleeding/spotting in order to avoid subsequent regular bleeding. In the subgroup of women in whom bleeding irregularities continue, sequential treatment should be considered.

A determination of the volumes of the layers of the rat hippocampal region.

The absolute volumes of the hippocampal and subicular cortical layers in the rat were determined. The boundaries of the various layers were defined on series of sections made through the entire hippocampal region of five rats and stained according to the Timm sulfide silver technique. Coordinates representing the boundaries of the layers on selected sections were fed into a mini-computer programmed to calculate the volume of the layers from the areas of the profiles and the distances between the sections. The distribution of the layers indicates that they constitute the same proportion of the volume of the dorsal and ventral divisions of the hippocampal region, with the exception of the structures lying in regio inferior and regio superior. Although the combined regio superior and regio inferior components of the layers of Ammon's horn occupy the same percentage of the volume of the dorsal and ventral hippocampal regions, the regio superior components occupy a larger percentage of Ammon's horn in the dorsal region than they do in the ventral region. The inter-animal variations in the volumes of the various layers indicate that it is possible to describe quantitatively the subdivisions of the hippocampal region with a precision that is compatible with comparative studies.