Reducing the burden of hypoglycaemia in people with diabetes through increased understanding: design of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project.

BACKGROUND: Hypoglycaemia is the most frequent complication of treatment with insulin or insulin secretagogues in people with diabetes. Severe hypoglycaemia, i.e. an event requiring external help because of cognitive dysfunction, is associated with a higher risk of adverse cardiovascular outcomes and all-cause mortality, but underlying mechanism(s) are poorly understood. There is also a gap in the understanding of the clinical, psychological and health economic impact of 'non-severe' hypoglycaemia and the glucose level below which hypoglycaemia causes harm. AIM: To increase understanding of hypoglycaemia by addressing the above issues over a 4-year period. METHODS: Hypo-RESOLVE is structured across eight work packages, each with a distinct focus. We will construct a large, sustainable database including hypoglycaemia data from >100 clinical trials to examine predictors of hypoglycaemia and establish glucose threshold(s) below which hypoglycaemia constitutes a risk for adverse biomedical and psychological outcomes, and increases healthcare costs. We will also investigate the mechanism(s) underlying the antecedents and consequences of hypoglycaemia, the significance of glucose sensor-detected hypoglycaemia, the impact of hypoglycaemia in families, and the costs of hypoglycaemia for healthcare systems. RESULTS: The outcomes of Hypo-RESOLVE will inform evidence-based definitions regarding the classification of hypoglycaemia in diabetes for use in daily clinical practice, future clinical trials and as a benchmark for comparing glucose-lowering interventions and strategies across trials. Stakeholders will be engaged to achieve broadly adopted agreement. CONCLUSION: Hypo-RESOLVE will advance our understanding and refine the classification of hypoglycaemia, with the ultimate aim being to alleviate the burden and consequences of hypoglycaemia in people with diabetes.

A randomized clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 1.

AIMS: The primary objective was to demonstrate that basal insulin peglispro (BIL) was non-inferior compared with insulin glargine (GL) for haemoglobin A1c (HbA1c) at 26 weeks with a non-inferiority margin of 0.4%. MATERIALS AND METHODS: IMAGINE 1 was a Phase 3, open-label, parallel-arm study conducted in nine countries. Adults with type 1 diabetes (n = 455) were randomized (2:1) to bedtime BIL or GL in combination with prandial insulin lispro for 78 weeks, with a primary endpoint of 26 weeks. An electronic diary facilitated data capture and insulin dosing calculations for intensive insulin management. RESULTS: At 26 weeks, mean HbA1c was 7.06% ± 0.04% and 7.43% ± 0.06% for patients assigned to BIL (N = 295) and GL (N = 160), respectively (difference -0.37% [95% CI: -0.50 to -0.23], P < .001); more patients on BIL achieved HbA1c <7% (44.9% vs 27.5%, P < .001). Compared with GL, patients using BIL lost weight, with lower fasting serum glucose and between-day fasting blood glucose variability, and 36% less nocturnal hypoglycemia, 29% more total hypoglycemia and more severe hypoglycemia. Total and prandial insulin doses were lower with BIL; basal insulin doses were higher. Alanine aminotransferase increased with BIL, with more patients having elevations ≥3 × ULN. BIL treatment was associated with more frequent injection site reactions and an increase from baseline in serum triglycerides. CONCLUSIONS: In patients with type 1 diabetes, treatment with BIL compared to GL for 26 weeks was associated with lower HbA1c, less nocturnal hypoglycemia, lower glucose variability and weight loss. Increases in total and severe hypoglycemia, triglycerides, aminotransferases and injection site reactions were also noted.

Randomized, double-blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 3.

AIMS: To compare the efficacy and safety of basal insulin peglispro (BIL), which has a flat pharmacokinetic and pharmacodynamic profile and a long duration of action, with insulin glargine (GL) in patients with type 1 diabetes. MATERIALS AND METHODS: In this phase III, 52-week, blinded study, we randomized 1114 adults with type 1 diabetes in a 3 : 2 distribution to receive either BIL (n = 664) or GL (n = 450) at bedtime, with preprandial insulin lispro, using intensive insulin management. The primary objective was to compare glycated haemoglobin (HbA1c) in the groups at 52 weeks, with a non-inferiority margin of 0.4%. RESULTS: At 52 weeks, mean (standard error) HbA1c was 7.38 (0.03)% with BIL and 7.61 (0.04)% with GL {difference -0.22% [95% confidence interval (CI) -0.32, -0.12]; p < 0.001}. At 52 weeks more BIL-treated patients reached HbA1c <7% (35% vs 26%; p < 0.001), the nocturnal hypoglycaemia rate was 47% lower (p < 0.001) and the total hypoglycaemia rate was 11% higher (p = 0.002) than in GL-treated patients, and there was no difference in severe hypoglycaemia rate. Patients receiving BIL lost weight, while those receiving GL gained weight [difference -1.8 kg (95% CI -2.3, -1.3); p < 0.001]. Treatment with BIL compared with GL at 52 weeks was associated with greater increases from baseline in levels of serum triglyceride [difference 0.19 mmol/l (95% CI 0.11, 0.26); p < 0.001] and alanine aminotransferase (ALT) levels [difference 6.5 IU/l (95% CI 4.1, 8.9), p < 0.001], and more frequent injection site reactions. CONCLUSIONS: In patients with type 1 diabetes, treatment with BIL compared with GL for 52 weeks resulted in a lower HbA1c, more patients with HbA1c levels <7%, and reduced nocturnal hypoglycaemia, but more total hypoglycaemia and injection site reactions and higher triglyceride and ALT levels.

Epidemiology of diabetic retinopathy: expected vs reported prevalence of cases in the French population.

AIM AND METHODS: Impaired eyesight and vision loss due to retinopathy are among the most feared complications in diabetic patients. As the number of diabetic patients is predicted to increase, a corresponding increase in the number of patients with diabetic retinopathy (DR) is also to be expected. This review is an update of the published literature pertaining to the epidemiology of DR. RESULTS: Over the past 20 years, eight population-based studies have been conducted in Western countries using photographic evidence of DR. Their results have consistently suggested that the prevalence of DR is close to 28.7%, whereas proliferative DR and macular oedema account for 9% and 17%, respectively, of all diagnosed cases. Various longitudinal studies indicate an annual incidence of DR of 2-6%. However, in France, the epidemiology of DR has mostly been investigated by observational studies. The recorded prevalence of DR, based on physicians' reports, is estimated to be 10%, suggesting that DR is underdiagnosed in the French diabetic population. The discrepancy between the expected and reported prevalences of DR could be explained by the number of patients whose retinal status is unknown. DR screening with non-mydriatic fundus photography is effective for identifying early and advanced DR. Screening programmes carried out over the past 5 years in different regions of France indicate that 10-20% of diabetic patients with previously unknown retinal status have retinopathy. CONCLUSION: Further implementation of screening programmes is the key to improving DR diagnosis and preventing vision loss in the French diabetic population.

Estimated prevalence of peripheral neuropathy and associated pain in adults with diabetes in France.

OBJECTIVE: To estimate the point prevalence of diabetic peripheral neuropathy (DPN) and pain associated with DPN (pDPN) in French adults with diabetes and compare severity of symptoms across demographic subpopulations. DESIGN: The participant-administered portion of the Michigan Neuropathy Screening Instrument (MNSI) and selected items of the Brief Pain Inventory (BPI) formed part of a computer-aided telephone survey posed to a representative, random sample of French households from March 1, 2005 to April 30, 2005. Questions from the MNSI and the BPI were used to assess the point prevalence of DPN and pDPN in French adults with self-reported diabetes. RESULTS: The mean age of the study sample was 68 years (SD = 15), the mean duration of diabetes was 15 years (SD = 12) and 56% of participants were female. The prevalence rates of DPN and pDPN in French adults with diabetes were 11 and 8%, respectively. The average age and diabetes duration of participants with DPN and pDPN were not different from participants in the total sample. Among those participants with pDPN, 35% classified their pain as severe, 49% as moderate, and 17% as mild. The prevalence of DPN was higher in participants with type 1 diabetes (14%) than those with type 2 (9%). Among participants with DPN, 88% with severe pain received pain treatment compared to 71% with moderate pain and 58% with mild pain. The most significant limitation of this study is the lack of validation for administering only a portion of the MNSI, but other limitations include the imprecision associated with self-reported questionnaires, a survey sample that does not include participants with undiagnosed diabetes, and a bias toward elderly participants. CONCLUSION: This study concluded that 8% of participants with diabetes in France had pDPN.

High incidence of SHOX anomalies in individuals with short stature.

OBJECTIVE: To study the SHOX gene and the PAR1 region in individuals with short stature. METHODS: The study involved 56 cases of dyschondrosteosis and 84 cases of idiopathic short stature (ISS). The study was designed to determine the following: the prevalence of SHOX anomalies in ISS; the frequency of Madelung deformity in individuals with SHOX anomalies; and the value of a family history of short stature in deciding whether to test for the SHOX gene. RESULTS: 54 SHOX anomalies were observed, including 42 (68%) in the dyschondrosteosis group and 12 (15%) in the ISS group. The high frequency of SHOX anomalies in the ISS group can be explained by the large proportion of boys in this group, reflecting the difficulty in diagnosing dyschondrosteosis in young boys. Clinical evidence of Madelung deformity in six parents of ISS individuals emphasised the importance of family evaluation. Among the 54 SHOX anomalies, 33 PAR1 deletions were identified encompassing the SHOX gene (62%), one partial intragenic deletion (2%), nine deletions located downstream of the SHOX gene (16%), and 11 point mutations (20%). CONCLUSIONS: These data emphasise the value of using microsatellite markers located within and downstream of the SHOX gene.

[The quality-of-life questionnaire QLS-H: validation of the French language version of the questionnaire in patients with growth hormone deficiency and collection of reference data in the general population]. / Le questionnaire de qualité de vie QLS-H: validation de la version française chez les patients avec déficit en hormone de croissance et acquisition des valeurs de référence dans la population générale.

The QLS-H(c) (Questions on Life Satisfaction- Hypopituitarism) is new a quality of life (QoL) self-administered questionnaire addressing the complaints of adult patients with growth hormone deficiency. The French version of the QLS-H(c) (16 items) has been psychometrically evaluated during a randomized, open label study comparing two strategies of growth hormone (GH) replacement therapy. Seventy-three patients were included and received an 8-month GH replacement therapy. QoL was explored at baseline, 4 and 8 months using the QLS-H(c) questionnaire and the Nottingham Health Profile (NHP) reference scale. Acceptance of the QLS-H(c) was excellent as 92% of the questionnaires were suitable for analysis. All the items demonstrated good selectivity. The homogeneity of the questionnaire was confirmed (Cronbach's alpha, 0.87). The external validity construct was assessed and confirmed using the NHP scores. Sensitivity to change was confirmed. Following an 8-month replacement therapy, the perception of the QoL assessed with the QLS-H(c) questionnaire was significantly improved, irrespective to the treatment strategy. Finally, redundant items of the questionnaire were removed. As a result, the final version of the QLS-H(c) contained 9 items. In a parallel study, reference data of the QLS-H(c) (9 items) were collected from a representative sample of 989 subjects from the French population. With these reference ranges, algorithms to calculate Z scores adjusted for age and gender were developed as a measure for the deviation of patients' scores from those of the general population, and also to evaluate changes along time. In summary, the French version of the quality of life QLS-H(c) questionnaire is a relevant, validated investigational tool for the evaluation and follow-up of an adult patient with growth hormone deficiency.

Post graft development of short children treated with growth hormone before kidney graft.

Sixteen prepubertal patients with chronic renal failure (CRF) were given daily recombinant human growth hormone (rhGH) treatment (1.2 IU/kg per week) for 2.6+/-1.6 years until kidney transplant. Therapy was then discontinued and the patients followed for a further 3. 5+/-1.4 years. During treatment, mean height increased from -3.0+/-0. 9 standard deviation score (SDS) to -1.9+/-1.4 SDS (P<0.001) at the time of transplantation, corresponding to a mean height gain of +1. 2+/-0.9 SDS. After discontinuation of rhGH therapy, prepubertal children continued a partial catch-up growth with a height gain of +0.5+/-0.8 SDS for the follow-up period. Conversely, negative changes of height were observed in pubertal transplanted children: -0.5+/-0.4 SDS in patients grafted at early stages of puberty (P2-P3) and -0.15+/-0.9 SDS in patients grafted at late stages of puberty (P4-P5). These data confirmed the benefit of rhGH therapy in CRF patients. Nevertheless, only early initiation of rhGH treatment led some of these patients to their target height at transplantation, thus preserving their potential growth. Reinitiation of rhGH therapy after transplantation should be considered in order to complete catch-up growth to target height in prepubertal children.

Low dose linomide in Type I juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial.

The quinoline-3-carboxamide, linomide, protects non-obese diabetic mice from diabetes. The effects of linomide on insulin needs and beta cell function were studied in recent juvenile Type I diabetes in a double-blind trial. Patients with recent onset diabetes were randomly assigned to treatment with a fixed dose of 2.5 mg linomide (42 patients) or placebo (21 patients) for 1 year, in addition to insulin and diet. Glycated haemoglobin was 10-15% lower at 9 months (p = 0.003) and 12 months (p < 0.05) in the linomide group. The insulin dose was 32-40% smaller in the linomide group at 3 (p < 0.03), 6 (p < 0.02), 9 (p < 0.001) and 12 months (p = 0.01). Insulin doses correlated negatively with C peptide values (p = 0.001-0.002). The trend for higher C peptide values in the linomide group did not reach significance. In a post hoc subgroup analysis performed in 40 patients (25 from the linomide group and 15 from the placebo group) who still had detectable residual beta cell function at entry, linomide was associated with 45-59% higher C peptide value at 6 months (p < 0.05), 9 months (p < 0.05) and 12 months (p < 0.05). The main adverse effects of linomide were mild transitory anaemia (45 vs 10% in the linomide and placebo groups), thrombocytopenia (24 vs 10%), and mild joint discomfort (45 vs 5%) with no clinical signs. In conclusion, low-dose linomide reduced the insulin needs in patients with juvenile Type I diabetes of recent onset and improved beta cell function in patients who still had detectable beta cell function at entry. These results support further clinical and experimental studies to define the effects of linomide in Type I diabetes provided the safety of linomide is reliably established.

Factors associated with glycemic control. A cross-sectional nationwide study in 2,579 French children with type 1 diabetes. The French Pediatric Diabetes Group.

OBJECTIVE: To determine on a large scale the multiple medical and nonmedical factors that influence glycemic control in the general population of children with diabetes, we performed a nationwide French cross-sectional study. RESEARCH DESIGN AND METHODS: We enrolled 2,579 patients aged 1-19 years with type 1 diabetes of > 1 year's duration. The study was center based: 270 centers were identified, 206 agreed to participate, and 147 included at least 90% of their patients. Questionnaires were completed by physicians interviewing patients and family, and HbA1c measurements were centralized. To identify explanatory variables for HbA1c level and frequency of severe hypoglycemia, we performed multiple regression analysis using all the quantitative variables collected and stepwise logistic regression for the qualitative variables. RESULTS: Mean HbA1c value for the whole population was 8.97 +/- 1.98% (normal 4.7 +/- 0.7% [SD]). Only 19 children (0.7%) had ketoacidosis during the 6 months before the study, whereas 593 severe hypoglycemia events occurred in 338 children (13.8%). Control was better in university-affiliated hospitals and centers following > 50 patients, reflecting the importance of access to experienced diabetologists. Children had a mean of 2.3 injections, allegedly performed 2.8 glucose measurements per day, and were seen an average of 4.6 times per year at the center. In the multiple regression analysis, 94% of the variance of HbA1c was explained by our pool of selected variables, with the highest regression coefficient between HbA1c and age (Rc = 0.43, P < 0.0001), then with daily insulin dosage per kilogram (Rc = 0.28, P < 0.0001), mother's age (Rc = 0.26, P < 0.0001), frequency of glucose measurements (Rc = 0.21, P < 0.0001), and diabetes duration (Rc = 0.14, P < 0.0001). Logistic regression identified quality of family support and dietary compliance, two related qualitative and possibly subjective variables, as additional explanatory determinants of HbA1c. The frequency of severe hypoglycemia was 45 per 100 patient-years and correlated with diabetes duration, but not with HbA1c levels or other variables. CONCLUSIONS: Although overall results remain unsatisfactory, 33% of studied French children with type 1 diabetes had HbA1c < 8%, the value obtained in Diabetes Control and Complications Trial adolescents treated intensively. Diabetes management in specialized centers should be encouraged.

Growth hormone treatment of children with short stature secondary to intra-uterine growth retardation: effect of 2 years' treatment and 2 years' follow-up.

Growth hormone (GH) treatment has been proposed to improve final height in patients with short stature associated with intra-uterine growth retardation (IUGR). In this study, 30 prepubertal patients aged 9.5 +/- 0.9 years with IUGR and normal GH secretion on pharmacological testing were treated with GH. These patients had a mean birth length of -3.11 +/- 0.80 SDS, and mean growth retardation of -2.58 +/- 0.49 SDS for chronological age. GH, 1.4 IU/kg/week (= 0.07 mg/kg/day), was given for 2 years. Height gain (calculated as the difference of height SDS at baseline and after 2 years) was 1.3 +/- 0.4 SD and was not significantly correlated with height SDS or growth velocity at baseline. These data confirm that 2 years of recombinant human GH treatment increases height gain in patients with IUGR. Two years after treatment interruption, mean gain was maintained at +1.08 SDS and 83% of the children had normal height.

Serotoninergic modulation of sodium appetite in the rat.

There are two mechanisms leading to an enhancement of salt intake: one is induced by a sodium deficit and the other is need-free. The serotonin involvement in need-induced and/or need-free sodium appetite is interesting to consider because related drugs are already used against another cardiovascular risk factor, obesity. The effect of dexfenfluramine (1.5 or 3 mg/kg), an anorectic drug enhancing 5-HT transmission, and of metergoline (2 or 4 mg/kg), a 5-HT antagonist, was assessed in need-induced (depletion-induced), subsequent need-free, and spontaneous sodium appetite. Dexfenfluramine (3 mg/kg) decreased by 75% to 90% the depletion-induced intake of an aversive 3% NaCl solution, as well as the spontaneous intake of a less aversive 1.8% NaCl solution. Water intake was not diminished under these conditions. Metergoline significantly increased salt intake in need-free conditions in rats with either a history of three previous depletions or not. These results confirm the involvement of serotonin in sodium appetite and extend this involvement to both need-induced (natriorexis) and need-free (natriophilia) conditions. The metergoline experiments also suggest that 5-HT exerts a tonic inhibition on salt intake.

Effects of thyroid status on thyroid autoimmunity expression in euthyroid and hypothyroid patients with Hashimoto's thyroiditis.

OBJECTIVE: In patients with hypothyroid goitrous Hashimoto's thyroiditis, the recovery from hypothyroidism seems to be due to a spontaneous decrease of antibodies (Ab) to the TSH-receptor (R). In contrast, in patients with Graves' disease made euthyroid by antithyroid drug therapy, the suppression of TSH secretion by thyroid hormone during antithyroid drug treatment decreases the production of Ab to TSH-R. We investigated in patients with initially euthyroid or hypothyroid goitrous Hashimoto's thyroiditis the relationships between thyroid status and the serum TSH-R, peroxidase (TPO) and thyroglobulin (Tg) Ab concentrations in untreated or L-thyroxine (T4) treated patients. PATIENTS: A prospective study of 174 consecutive patients, referred with goitrous Hashimoto's disease in an initially euthyroid (group I, n = 78) or hypothyroid (group II, n = 96) state. The patients with positive (> or = 7%) TSH-RAb (group I, n = 18; group II, n = 22) were reinvestigated 12 months after the initiation of L-T4 therapy. After which, (1) L-T4 was continued and an evaluation performed 2 months later (i.e. 14 months after L-T4 initiation) in 9 patients of group I and in 11 patients of group II or (2) L-T4 was withdrawn and an evaluation performed 2 months later in 9 patients of group I and in 11 patients of group II. MEASUREMENTS: Measurements of basal plasma TSH, free T4 (FT4) and total T3 and serum TSH-R, TPO and TgAb. RESULTS: The prevalence of positive TSH-RAb levels did not differ between group I (23.1%) and group II (22.9%). However, the mean TSH-RAb level in group I (9.4 +/- 0.4%) was lower (P < 0.01) than in group II (11.6 +/- 0.5%). In the patients with positive TSH-R Ab, (1) the prevalences of positive TSH-RAb decreased (P < 0.001) under L-T4 therapy (group I = 22.2%, group II = 21.2%) and increased again (P < 0.01) 2 months after L-T4 cessation (group I = 77.7%, group II = 63.6%) to reach lower levels (group I, P < 0.05; group II, P < 0.01) than those obtained prior to L-T4 treatment. Statistical analysis of TSH levels through the course of the study confirmed these results. (2) In contrast to the variations of the mean TgAb values, the variations of the mean TPOAb levels in each group were in good agreement with those of TSH-RAb through the course of the study. (3) There were significant correlations between some parameters of thyroid status and both TSH-RAb (TSH, r = 0.43, P < 0.001; FT4, r = -0.35, P < 0.01) and TPOAb (TSH, r = 0.42, P < 0.001; FT4, r = -0.31; P < 0.01) levels. In contrast, no correlations were found between thyroid status and TgAb values. CONCLUSIONS: This study demonstrates that thyroid status can modulate thyroid autoimmunity expression, such as TSH-RAb and TPOAb, in patients with euthyroid or hypothyroid goitrous Hashimoto's thyroiditis. Similar results have been reported in patients with Graves' disease made euthyroid by the administration of thyroid hormone during antithyroid drug treatment.

Paradoxical effect of somatostatin analogues on the ectopic secretion of corticotropin in two cases of small cell lung carcinoma.

We investigated 2 patients affected with Cushing's syndrome due to the ectopic production of adrenocorticotropic hormone (ACTH) by a small cell lung carcinoma. In the 2 patients, the long-acting somatostatin analogue octreotide (100 micrograms, subcutaneously) induced a paradoxical increase in plasma ACTH and cortisol levels. In 1 patient, lanreotide, a new somatostatin analogue in a slow-release formulation (30 mg, intramuscularly), induced a similar rise in ACTH and cortisol secretion. To our knowledge, such a response has not been previously reported. Further use of somatostatin analogues in ectopic ACTH-producing tumors, especially lung tumors, requires preliminary evaluation of their therapeutic efficacy by a short test with somatostatin analogue.