Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes.

AIMS: To compare the glycaemic control of an insulin lispro mixture (25% insulin lispro and 75% NPL) twice daily in combination with metformin to that of once-daily insulin glargine plus metformin in patients with Type 2 diabetes inadequately controlled with intermediate insulin, or insulin plus oral agent(s) combination therapy. RESEARCH DESIGN AND METHODS: Ninety-seven patients were randomized in a multicentre, open-label, 32-week crossover study. Primary variables evaluated: haemoglobin A1c (A1c), 2-h post-prandial blood glucose (BG), hypoglycaemia rate (episodes/patient/30 days), incidence (% patients experiencing > or = 1 episode) of overall and nocturnal hypoglycaemia. RESULTS: At endpoint, A1c was lower with the insulin lispro mixture plus metformin compared with glargine plus metformin (7.54% +/- 0.87% vs. 8.14% +/- 1.03%, P < 0.001). Change in A1c from baseline to endpoint was greater with the insulin lispro mixture plus metformin (-1.00% vs. -0.42%; P < 0.001). Two-hour post-prandial BG was lower after morning, midday, and evening meals (P < 0.001) during treatment with the insulin lispro mixture plus metformin. The fasting BG values were lower with glargine plus metformin (P = 0.007). Despite lower BG at 03.00 hours (P < 0.01), patients treated with the insulin lispro mixture plus metformin had a lower rate of nocturnal hypoglycaemia (0.14 +/- 0.49 vs. 0.34 +/- 0.85 episodes/patient/30 days; P = 0.002), although the overall hypoglycaemia rate was not different between treatments (0.61 +/- 1.41 vs. 0.44 +/- 1.07 episodes/patient/30 days; P = 0.477). CONCLUSION: In patients with Type 2 diabetes and inadequate glucose control while on insulin or insulin and oral agent(s) combination therapy, treatment with a twice-daily insulin lispro mixture plus metformin, which targets both post-prandial and pre-meal BG, provided clinically significant improvements in A1c, significantly reduced post-prandial BG after each meal, and reduced nocturnal hypoglycaemia as compared with once-daily glargine plus metformin, a treatment that targets fasting BG.

Efficacy of Humalog injections before an afternoon meal and their acceptance by children and adolescents with type 1 diabetes.

AIMS: To evaluate the acceptability and efficacy of an injection of insulin lispro, before an afternoon meal. METHODS: The subjects, 43 patients with Type 1 diabetes, 16 boys and 27 girls, aged 12.4 +/- 2.4 years, were randomly assigned to the treatment (n = 20) or the untreated control group (n = 23). The treatment was an injection of insulin lispro immediately before the afternoon meal. The control group had no injection. The treatment and the control group consumed identical types of meals for 2 months. The mean before-dinner blood glucose was measured during the last 2 weeks of the study. RESULTS: Injection of insulin lispro resulted in a significant reduction in the before-dinner blood glucose compared with the untreated control group (10.4 +/- 3.8 mmol/l vs. 14.7 +/- 3.9 mmol/l, respectively). The number of days on which the blood glucose was > 10 mmol/l was reduced by half in the insulin lispro group. The difference in HbA1c between baseline and endpoint differed slightly but significantly between the two groups, in boys. Treated patients ate the meal less frequently (11.4 +/- 3.0 times per 15 days) than the control patients (14.4 +/- 0.6 times per 15 days) and injected themselves with insulin 8.9 +/- 3.6 times per 15 days. The HbA1c increased significantly with the number of meals taken without injection. There was no statistically significant difference in the frequency of hypoglycaemia or changes in weight between the two groups. CONCLUSIONS: We conclude that an injection of insulin lispro before the afternoon meal can effectively lower the before-dinner blood glucose, and in boys also lowers the HbA1c. Patients were satisfied with the lower blood glucose before dinner, and did not find the insulin lispro injection difficult. However, compliance with the protocol procedures decreased during a subsequent 6-month period.

Which are the insulin treatment regimens used in France? The "Schema survey".

OBJECTIVE: To examine how insulin therapy is used in France under real life conditions for type 1 and insulin-treated type 2 patients. MATERIAL AND METHODS: The "Schema survey" was a cross-sectional survey carried out for all the insulin-treated patients seen by participating physicians on a given day. All registered diabetologists in France were invited to participate, 934 initially agreed, 450 returned at least one questionnaire. These 450 physicians appeared to be representative of the whole. The reasons for which 484 physicians who had initially agreed to participate did not were collected by telephone and do not seem to introduce a bias. 1,263 patients were included in the analysis, type 1: 57.6%, type 2: 36.8%. RESULTS: Over 54% of type 1 patients were treated with 3 or more insulin injections per day. Among type 1 patients treated with 2 injections per day, 30% were younger than 18. Over 82% type 2 patients were treated with 1 or 2 insulin injections per day. A regimen combining oral agents and bed time NPH was used in 18% of type 2 patients. Premixed insulins were used by 45.5% of type 2 and 39.5% of type 1 patients. For patients under 3 or more injections per day, over 30 different regimens were identified. About 40% of patients, either type 1 or 2, were poorly controlled (HbA1c > 8.5%). The frequency of blood glucose monitoring appears to comply with recommendations. CONCLUSIONS: Under real life conditions, a majority of French type 1 patients are treated with intensified multiple injections but a lot are not, despite inadequate metabolic control. Only few type 2 patients are treated with intensified therapy.

[Frequency and costs of hospital stays for hypoglycemia in France in 1995]. / Fréquence et coûts des séjours hospitaliers pour hypoglycémie en France en 1995.

OBJECTIVES: Diabetes is a highly prevalent chronic disease causing serious complications. Hypoglycemia is the most frequent, the most serious, and the most feared by patients and families. Hospitalization may be necessary and can be costly. The main objective of this study was to determine the number of cases of hypoglycemia cared for annually in France in an inpatient setting and to estimate the annual financial impact of hospitalizations. PATIENTS AND METHODS: The number of hypoglycemias seen annually by physician s in France and the frequencies of hospitalizations for hypoglycemia were determined from a literature search. Complementary data on costs were obtained from the national PMSI mission. Our sample included 817 hospital stays between 1994 and 1995. RESULTS: In 1992, physicians in France cared for 40,000 episodes of hypoglycemia. There were 10,800 hospitalizations. In 9 out of 10 cases, the hospital stay lasted several days and, despite hospitalization, 1.9% of the patients died. Mean total medical cost of a hospital stay for hypoglycemia was 14,000 FF ($2,100) (median 10,000 FF, range 1,200-120,000 FF). Mean length of stay was 6.6 days. DISCUSSION: Mean unit cost for hospital stays for hypoglycemia is high. Based on the 1993 SESI survey, the probable annual cost for the society for hospital care of patients with hypoglycemia was an estimated 108 to 151 million FF ($16-22 million) in 1995. This figure only takes into account the visible cost of caring for hypoglycemia patients. Ambulatory care was not taken into consideration. Education, for the patient and family, is fundamental for the prevention and treatment of hypoglycemia. CONCLUSION: It is important to have this estimation due to the absence of a medicoeconomic study on ambulatory and hospital care for hypoglycemia. Complementary studies should be conducted to estimate the total annual cost of hypoglycemia in France.

[Results of international clinical trials with raloxifene]. / Résultats des études cliniques internationales du raloxifène.

A new drug class called Selective Estrogen Receptor Modulators (SERM) could combine ideal properties for a product designed for menopausal women. The most widely studied member of this class is raloxifene which is currently marketed in several countries for the prevention of osteoporosis in menopaused women. This product is a nonsteroidal derivative of benzothiophene which, like estrogens, has a preventive effect against bone loss involving the spine and peripheral skeleton and a cholesterol lowering effect, both in the ovariectomized rat and in menopausal women. Unlike estrogens, raloxifene does not stimulate breast or uterine tissue. These interesting properties make raloxifene a possible preventive treatment for osteoporosis and other menopause-related risks for menopausal women of all ages. Multicenter studies have been conducted in recently menopausal women who received either raloxifene at the doses of 30, 60, or 150 mg/day or a placebo in a randomized protocol. All subjects were also given calcium supplementation. Bone density was measured twice a year for 36 months by dual X-rays absorptiometry and showed a significant decrease at all sites in the placebo group while there was a significant increase in the spine, the hip and the overall skeleton for all three raloxifen groups. After 24 months of treatment, mean increase over placebo was 2.4% for 60 mg raloxifene measured on the spine and total hip and 2% for the overall skeleton. Markers of bone formation (serum osteocalcin and bone alkaline phasphatase) and resorption (urinary CrossLaps) decreased significantly reaching, after 3 to 6 months of treatment, the levels observed in non menopausal women. In addition, total serum cholesterol as well as LDL-cholesterol decreased significantly in a dose-dependent fashion in all groups treated with raloxifene. Serum HDL-cholesterol and triglycerides did not very significantly during treatment. Hot flashes were the most frequently observed undesirable effect, at a frequency slightly higher in the raloxifene group (25%) than in the placebo group (18%). This undesirable effect was of low intensity and generally occurred during the first months of treatment. It did not cause a higher drop out rate (raloxifen 1.5%; placebo 2.1%). The preliminary data at two years follow-up suggest that raloxifene is not associated with an increased risk of breast cancer. In conclusion, raloxifene is a particularly interesting drug for menopausal women showing very promising efficacy and clinical tolerance.

Improvement of HbA1c and blood glucose stability in IDDM patients treated with lispro insulin analog in external pumps.

OBJECTIVE: To compare the efficacy of the short-acting insulin analog lispro (LP) with that of regular insulin in IDDM patients treated with an external pump. RESEARCH DESIGN AND METHODS: Thirty-nine IDDM patients (age, 39.4 +/- 1.5 years; sex ratio, 22M/17W; BMI, 24.4 +/- 0.4 kg/m2; diabetes duration, 22.5 +/- 1.6 years) who were treated by external pump for 5.1 +/- 0.5 years were involved in an open-label, randomized, crossover multicenter study comparing two periods of 3 months of continuous subcutaneous insulin infusion with LP or with Actrapid HM, U-100 (ACT). Boluses were given 0-5 min (LP) or 20-30 min (ACT) before meals. Blood glucose (BG) was monitored before and after the three meals every day. RESULTS: The decrease in HbA1c was more pronounced with LP than with ACT (-0.62 +/- 0.13 vs. -0.09 +/- 0.15%, P = 0.01). BG levels were lower with LP (7.93 +/- 0.15 vs. 8.61 +/- 0.18 mmol/l, P < 0.0001), particularly postprandial BG levels (8.26 +/- 0.19 vs. 9.90 +/- 0.20 mmol/l, P < 0.0001). Standard deviations of all the BG values (3.44 +/- 0.10 vs. 3.80 +/- 0.10 mmol/l, P = 0.0001) and of postprandial BG values (3.58 +/- 0.10 vs. 3.84 +/- 0.10 mmol/l. P < 0.02) were lower with LP. The rate of hypoglycemic events defined by BG < 3.0 mmol/l did not significantly differ between LP and ACT (7.03 +/- 0.94 vs. 7.94 +/- 0.88 per month, respectively), but the rate of occurrences of very low BG, defined as BG < 2.0 mmol/l, were significantly reduced with LP (0.05 +/- 0.05 vs. 0.47 +/- 0.19 per month, P < 0.05). At the end of the study, all but two (95%) of the patients chose LP for the extension phase. CONCLUSIONS: When used in external pumps, LP provides better glycemic control and stability than regular insulin and does not increase the frequency of hypoglycemic episodes.

GnRH receptors in human granulosa cells: anatomical localization and characterization by autoradiographic study.

The presence of receptors for GnRH in human ovary has been investigated by quantitative autoradiography. Simultaneous visualization and characterization of specific receptors on frozen sections were obtained on six pairs of human ovaries. Among them only one exhibited a large preovulatory follicle. This dominant follicle exhibited a specific and high affinity binding capacity for 125I-GnRHa exclusively localized on the granulosa cell layer. Analysis of saturation curve indicates a Kd value of 0.22 nM and Bmax of 9.6 fmol/mg protein. In contrast LH-hCG binding sites were present in all antral follicles. These data demonstrate for the first time the presence of high affinity GnRH receptors in human granulosa cells at a late stage of follicular maturation.