Comparison of insulin glargine and liraglutide added to oral agents in patients with poorly controlled type 2 diabetes.

AIM: To compare safety and efficacy of insulin glargine and liraglutide in patients with type 2 diabetes (T2DM). METHODS: This randomized, multinational, open-label trial included subjects treated for T2DM with metformin ± sulphonylurea, who had glycated haemoglobin (HbA1c) levels of 7.5-12%. Subjects were assigned to 24 weeks of insulin glargine, titrated to target fasting plasma glucose of 4.0-5.5 mmol/L or liraglutide, escalated to the highest approved clinical dose of 1.8 mg daily. The trial was powered to detect superiority of glargine over liraglutide in percentage of people reaching HbA1c <7%. RESULTS: The mean [standard deviation (s.d.)] age of the participants was 57 (9) years, the duration of diabetes was 9 (6) years, body mass index was 31.9 (4.2) kg/m(2) and HbA1c level was 9.0 (1.1)%. Equal numbers (n = 489) were allocated to glargine and liraglutide. Similar numbers of subjects in both groups attained an HbA1c level of <7% (48.4 vs. 45.9%); therefore, superiority of glargine over liraglutide was not observed (p = 0.44). Subjects treated with glargine had greater reductions of HbA1c [-1.94% (0.05) and -1.79% (0.05); p = 0.019] and fasting plasma glucose [6.2 (1.6) and 7.9 (2.2) mmol/L; p < 0.001] than those receiving liraglutide. The liraglutide group reported a greater number of gastrointestinal treatment-emergent adverse events (p < 0.001). The mean (s.d.) weight change was +2.0 (4.0) kg for glargine and -3.0 (3.6) kg for liraglutide (p < 0.001). Symptomatic hypoglycaemia was more common with glargine (p < 0.001). A greater number of subjects in the liraglutide arm withdrew as a result of adverse events (p < 0.001). CONCLUSION: Adding either insulin glargine or liraglutide to subjects with poorly controlled T2DM reduces HbA1c substantially, with nearly half of subjects reaching target levels of 7%.

Modulation of insulin dose titration using a hypoglycaemia-sensitive algorithm: insulin glargine versus neutral protamine Hagedorn insulin in insulin-naïve people with type 2 diabetes.

AIMS: To examine whether insulin glargine can lead to better control of glycated haemoglobin (HbA1c) than that achieved by neutral protamine Hagedorn (NPH) insulin, using a protocol designed to limit nocturnal hypoglycaemia. METHODS: The present study, the Least One Oral Antidiabetic Drug Treatment (LANCELOT) Study, was a 36-week, randomized, open-label, parallel-arm study conducted in Europe, Asia, the Middle East and South America. Participants were randomized (1:1) to begin glargine or NPH, on background of metformin with glimepiride. Weekly insulin titration aimed to achieve median prebreakfast and nocturnal plasma glucose levels ≤5.5 mmol/l, while limiting values ≤4.4 mmol/l. RESULTS: The efficacy population (n = 701) had a mean age of 57 years, a mean body mass index of 29.8 kg/m², a mean duration of diabetes of 9.2 years and a mean HbA1c level of 8.2% (66 mmol/mol). At treatment end, HbA1c values and the proportion of participants with HbA1c <7.0 % (<53 mmol/mol) were not significantly different for glargine [7.1 % (54 mmol/mol) and 50.3%] versus NPH [7.2 % (55 mmol/mol) and 44.3%]. The rate of symptomatic nocturnal hypoglycaemia, confirmed by plasma glucose ≤3.9 or ≤3.1 mmol/l, was 29 and 48% less with glargine than with NPH insulin. Other outcomes were similar between the groups. CONCLUSION: Insulin glargine was not superior to NPH insulin in improving glycaemic control. The insulin dosing algorithm was not sufficient to equalize nocturnal hypoglycaemia between the two insulins. This study confirms, in a globally heterogeneous population, the reduction achieved in nocturnal hypoglycaemia while attaining good glycaemic control with insulin glargine compared with NPH, even when titrating basal insulin to prevent nocturnal hypoglycaemia rather than treating according to normal fasting glucose levels.

Physical characteristics that predict final basal insulin dose in type 2 diabetes mellitus, with a special focus on BMI.

BACKGROUND AND AIMS: The possibility to predict final insulin dose based on patient's characteristics would allow for efficient titration for patients with higher dose needs. The primary aim of this post-hoc analysis of the L2T3 study was to determine predictors for final dose. Specifically, we focused on the relationship between BMI and dose. The secondary aims were to investigate (i) the predictive value of BMI and age on final dose and (ii) the possibility to tailor the starting dose of insulin based on BMI and age. METHODS AND RESULTS: We performed two stepwise regression analyses, one using all baseline characteristics, and one using physical characteristics and FPG which can be assessed "at the bedside" only. Furthermore, median [min, max] final doses of groups stratified according to BMI and age were calculated. BMI clearly correlated with final dose in IU (Pearson correlation 0.42 [0.37; 0.48], p < 0.001). Characteristics which can be assessed "at the bedside" that predict high final dose were allocation to detemir, absence or discontinuation of insulin secretagogues, high BMI, low age, male gender and high FPG. Final dose varied among strata (BMI ≥30 kg/m(2): 64 IU; BMI <30 kg/m(2): 38 IU, p < 0.001 and age <59 years: 52 IU; age ≥59 years: 44 IU, p < 0.001). All groups stratified for both BMI and age showed similarly low minimal final dose (5-17 IU). CONCLUSION: Our data showed a high predictive value of BMI on final dose. However, it does not seem possible to tailor starting dose based on BMI and age.

Primary-care observational database study of the efficacy of GLP-1 receptor agonists and insulin in the UK.

AIMS: We investigated use and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in UK practice. METHODS: People starting a GLP-1 receptor agonist (exenatide, liraglutide) or insulin (glargine, detemir, NPH) after a regimen of two or three oral glucose-lowering agents were identified from The Health Information Network observational primary care database (2007-2011). Mean change in HbA1c and body weight were compared at 1 year between cohorts, adjusting for baseline characteristics. RESULTS: Baseline characteristics of GLP-1 receptor agonist (n = 1123) vs. insulin (n = 1842) users were HbA1c 78 vs. 84 mmol/mol (9.3 vs. 9.8%) and BMI 38.2 vs. 30.9 kg/m². The GLP-1 receptor agonist cohort was younger, had shorter diabetes duration and follow-up, less microvascular disease and heart failure, higher estimated glomerular filtration rate and more use of oral glucose-lowering agents. Lower HbA1c reduction on GLP-1 receptor agonist [7 vs. 13 mmol/mol (0.6 vs. 1.2%) (n = 366 vs. 892)] was not statistically significant [adjusted mean difference -1.4 (95% CI -4.1, 1.2) mmol/mol], except in the highest HbA1c quintile [>96 mmol/mol (>10.9%); adjusted mean difference -17.8 (-28.6, -7.0) mmol/mol]. GLP-1 receptor agonist users lost weight [-4.5 vs. +1.5 kg; adjusted mean difference 4.7 (3.7, 5.8) kg; n = 335 vs. 634]. A UK 6-month target reduction for GLP-1 receptor agonists of 11 mmol/mol (1.0%) HbA1c and 3% weight was reached by 24.9% of those continuing treatment. CONCLUSIONS: Those starting GLP-1 receptor agonists are heavier with better glycaemic control than those starting basal insulin. Subsequently, they have improved weight change, with similar HbA1c reduction unless baseline HbA1c is very high. The UK 6-month GLP-1 receptor agonist target is usually not reached.

A comparison of duration of first prescribed insulin therapy in uncontrolled type 2 diabetes.

AIMS: We investigated whether differences in duration of first insulin use in type 2 diabetes remain after adjustment for potential confounders, and what factors are associated with longer use. METHODS: People prescribed a first insulin (2000-2007) after 2-3 non-insulin glucose lowering treatments (OGLD) were identified from the THIN UK primary care database and grouped by insulin, detemir (n=165), glargine (n=1011) or NPH (n=420). Time from beginning insulin to the prescription of another insulin type or a glucagon-like peptide was compared between insulins in a Cox model adjusting for: demographics, HbA1c, history of vascular complications and cardiovascular risk factors. The strength of association between duration of use and these variables was investigated. RESULTS: The adjusted hazard ratios compared to glargine for treatment change were 1.58 (95% CI 1.25, 2.00) for detemir and 1.49 (1.25, 1.78) for NPH. Lower mean treatment HbA(1c) correlated with longer time to a different insulin regimen (Spearman rank correlation -0.30, p<0.01) as were continuing OGLDs, older age, longer time from diagnosis, lower body mass index, lower HbA(1c), and no heart failure at baseline. CONCLUSIONS: People who began treatment with glargine and those with better on-treatment HbA(1c) remained on their first insulin for longer than those who began detemir or NPH.

Two-year glycaemic control and healthcare expenditures following initiation of insulin glargine versus neutral protamine Hagedorn insulin in type 2 diabetes.

AIMS: To compare 2-year glycaemic control, hypoglycaemia and healthcare expenditures following insulin glargine (glargine, n = 2105) or neutral protamine Hagedorn (NPH) insulin (NPH, n = 734) initiation in patients with type 2 diabetes (T2D). METHODS: Retrospective cohort study using an integrated US health insurance administrative database was conducted. Individuals with a diabetes diagnostic claim and initiated basal insulin therapy with glargine or NPH from 2001 to 2005 dispensed at least one oral antidiabetic drug prescription during 6 months prior to basal insulin initiation and enrolled in the same health insurance plan from 6 months before to 12 months or more after insulin initiation were identified. Repeated measures mixed-effects models evaluated glycaemic and financial outcomes to account for factors potentially contributing to selection of insulin therapy, that is, age, gender, baseline HbA1c level, health expenditures, co-morbidities, healthcare utilization, pharmacy co-payment and follow-up antidiabetic medications. RESULTS: Adjusted mean HbA1c value in the first year following insulin initiation was significantly lower for glargine versus NPH initiators (Δ = -0.43, p = 0.006); this difference diminished in the second year (Δ = -0.16, p = 0.375). First-year adjusted quarterly hypoglycaemia incidence rates were lower for glargine (2.1%) versus NPH (2.4%) (p = 0.02) as was the second-year quarterly rate (1.8 vs. 2.2%; p = 0.01). Both the first- and second-year adjusted total healthcare expenditures were lower in the glargine versus NPH group (year 1: $18,720 vs. $19,996, p = 0.005; year 2: $15,008 vs. $17,336; p < 0.001). CONCLUSIONS: Glargine therapy may be an effective long-term option for improving glycaemic control, with lower rates of hypoglycaemia and healthcare costs in patients with T2D.

Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes.

We compared the combined use of basal insulin, metformin and insulin secretagogues with a combination of basal insulin and metformin in patients with type 2 diabetes starting basal insulin analogue therapy. This analysis was part of a 24-week trial, in which 964 insulin-naive patients with type 2 diabetes inadequately controlled on oral agents (including metformin) were randomized to insulin glargine or detemir. Secretagogues were stopped or maintained at the site-investigators' discretion. During the study, 57.6% of patients continued their secretagogue treatment. Compared with patients stopping secretagogues, those who continued experienced significantly more hypoglycaemia and weight gain. Insulin doses, however, were significantly lower: 0.6 ± 0.4 versus 0.8 ± 0.4 U/kg/day (p < 0.001). The difference between groups in mean HbA1c reduction was not statistically significant. In conclusion, in type 2 diabetic patients starting basal insulin analogue therapy, continuing both metformin and secretagogues results in more hypoglycaemia and weight gain and lower insulin doses than only maintaining metformin.

Insulin glargine provides greater improvements in glycaemic control vs. intensifying lifestyle management for people with type 2 diabetes treated with OADs and 7-8% A1c levels. The TULIP study.

AIM: To determine whether earlier administration of insulin glargine (glargine) vs. the intensification of lifestyle management (LM) improves glycaemic control in type 2 diabetes patients with A1c 7-8% treated with oral therapy. METHODS: TULIP [Testing the Usefulness of gLargine when Initiated Promptly in type 2 diabetes mellitus (T2DM)] was a 9-month, 12-visit, open-label, multinational, multicentre, randomized study to evaluate starting glargine or intensifying LM in T2DM patients aged 40-75 years, body mass index (BMI) 24-35 kg/m2 and A1c 7-8%, treated with maximum doses of metformin and sulphonylurea for > or = 2 years. Glargine was injected once daily (evening) and titrated to fasting blood glucose 0.7-1.0 g/l. In the LM arm, dietary and physical activity counselling recommended stable weight for people with BMI < 27 kg/m2 or weight loss of 3 kg for patients with BMI > or = 27 kg/m2. A total of 215 patients were randomized to glargine (n = 106) or LM (n = 109). The primary objective was patients achieving A1c < 7% at endpoint. Secondary endpoints included changes in A1c, in fasting plasma glucose (FPG), body weight and hypoglycaemia incidence. RESULTS: Two hundred and eleven (52.6% male) patients were randomized and treated; mean (+/- s.d.) age 60.7 +/- 7.9 years, weight 84.5 +/- 13.1 kg, BMI 29.9 +/- 3.5 kg/m2 and A1c 7.6 +/- 0.4%. More patients reached A1c < 7% (66 vs. 38%; p < 0.0001) or < 6.5% (34 vs. 11%; p = 0.0001) with glargine vs. LM. The change in FPG from baseline to study endpoint was significantly greater in the glargine vs. the LM arm (-0.50 +/- 0.47 vs. -0.05 +/- 0.39 g/l respectively; p < 0.0001). Compared with the glargine group, the LM group showed a decrease in weight (+0.9 +/- 2.9 vs. -2.5 +/- 3.2 kg; p < 0.0001), as well as the expected lower symptomatic hypoglycaemia (55.3 vs. 25.0%; p < 0.0001) and nocturnal hypoglycaemia (20.4 vs. 5.6%; p = 0.0016). No significant changes were observed from baseline to study endpoint in any of the lipid parameters tested. CONCLUSIONS: In patients with T2DM with A1c 7-8%, who were previously treated by conventional LM and OAD therapy, adding glargine resulted in greater improvements in glycaemic control vs. intensifying LM.

Three-year follow-up of the use of transdermal 17beta-estradiol matrix patches for the prevention of bone loss in early postmenopausal women.

OBJECTIVE: A total of 325 of 569 postmenopausal women who were initially recruited into two 2-year, double-blind, placebo-controlled, dose-ranging studies of a matrix transdermal formulation of 17beta-estradiol (Menorest) participated in open-label extensions for a third year. STUDY DESIGN: Those patients originally randomly assigned to receive 17beta-estradiol continued active treatment with dosages of 25, 50, 75, or 100 microg/d, whereas those originally randomly assigned to receive a placebo patch were switched to an active patch of identical size that delivered 17beta-estradiol at 25, 50, 75, or 100 microg/d. Follow-up was conducted, and bone density and other parameters were compared. RESULTS: Overall, gains in bone mass were maintained in patients who received 3 years of active treatment. In patients originally randomly assigned to receive placebo, initial losses in bone mass during the first 2 years were reversed and replaced with marked increases after the switch to active treatment. All patients who had initially received placebo showed significant, dose-related, clinically relevant increases (2.77% +/- 0.99%; P =.0048; to 7.36% +/- 0.74%; P =.0001) in lumbar spine bone mineral density relative to the end of the second year of the original study; smaller final-year increases were noted among the patients who had been actively treated for all 3 years. Similar trends were reported for femoral, trochanter, and total hip bone mineral densities. Mean total body bone mineral density either increased or remained unchanged in all dosage groups. These results were accompanied by parallel changes in levels of serum and urinary markers of bone turnover, with all markers approaching or returning to premenopausal levels by month 36. The high tolerability of this formulation during years 1 and 2 was maintained during year 3; 5.5% of patients withdrew from treatment because of adverse events in the final year. CONCLUSION: The Menorest formulation of transdermal 17beta-estradiol maintained bone mineral density gains in postmenopausal women and was well tolerated through a 3-year treatment period. It was also effective in reversing the initial bone loss associated with late commencement of therapy.

Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause.

OBJECTIVE: This study was undertaken to evaluate the efficacy and tolerability of a combination estradiol plus norethindrone acetate transdermal delivery system given in a continuous sequential regimen with transdermal estradiol versus placebo in the treatment of vasomotor symptoms of menopause. STUDY DESIGN: This was a 12-week double-blind trial of 220 healthy postmenopausal women with > or = 8 moderate to severe hot flushes and sweating episodes per day. Women were randomly assigned to wear transdermal placebo patches or a transdermal patch releasing 50 microg/d 17beta-estradiol alone (Vivelle) for days 1 to 14 of each cycle and a combination patch releasing 50 microg/d 17beta-estradiol plus 1 of 3 dosage levels (140, 250, or 400 microg/d) of norethindrone acetate (CombiPatch) for days 15 through 28. RESULTS: There was a significant (P <.001) reduction by the second week in the mean number of daily hot flushes from baseline to end point with all 3 doses of estradiol plus norethindrone acetate compared with placebo. Significant (P <.001) reductions in the mean intensity of hot flushes and sweating were also noted with estradiol plus norethindrone acetate compared with placebo. The incidences of adverse events with all 3 doses of estradiol plus norethindrone acetate and with placebo were comparable. CONCLUSION: An estradiol plus norethindrone acetate transdermal delivery system administered in a continuous sequential regimen with transdermal estradiol was well tolerated and effective for the treatment of moderate to severe vasomotor symptoms in postmenopausal women.

Matrix delivery transdermal 17beta-estradiol for the prevention of bone loss in postmenopausal women. The International Study Group.

A total of 277 early postmenopausal women were enrolled in this placebo-controlled 2-year study to examine the efficacy of a matrix transdermal 17beta-estradiol system, at three different dosages (25, 50 and 75 mg/day) combined with sequential oral dydrogesterone 20 mg/day, in preventing bone loss. At 2 years, the difference from placebo in percentage change from baseline of L1-4 lumbar spine bone mineral density (BMD) (assessed by dual-energy X-ray absorptiometry) was 4.7% +/- 0.7% with estradiol 25 mg/day, 7.3% +/- 0.7% with estradiol 50 mg/day and 8.7% +/- 0.7% with estradiol 75 mg/day (all values mean +/- SEM). There were also significant increases in femoral neck, trochanter and total hip BMD with all doses of estradiol compared with placebo. Additionally, most patients had a significant gain (increase greater than 2.08%) in lumbar spine bone mass compared with placebo. Patients who received estradiol also experienced clinically significant and dose-related decreases in total serum osteocalcin, serum bone alkaline phosphatase and urinary C-telopeptide, with all three markers of bone turnover returning to premenopausal levels. Estradiol was well tolerated during the 2-year treatment period. Transdermal estradiol is effective and well tolerated at dosages between 25-75 mg/day in the prevention of bone loss in postmenopausal women; 25 mg/day offers an effective option for those women who cannot tolerate higher doses.

A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group.

OBJECTIVE: To determine whether a continuous estradiol-norethindrone acetate transdermal delivery system reduces incidence of endometrial hyperplasia in postmenopausal women more than transdermal estradiol (E2) alone. METHODS: Six hundred twenty-five postmenopausal women were assigned randomly to one of four treatments, transdermal E2 50 microg/day, or transdermal E2-norethindrone acetate with 50 microg E2 and 140, 250, or 400 microg/day of norethindrone acetate. Follow-up visits to collect information on safety and efficacy were scheduled at 3, 6, 9, and 12 months after initiation of treatment. Endometrial biopsy for histologic evaluation was done at baseline and upon exit from the study (completion or withdrawal). Endometrial histology was evaluated by two independent gynecologic pathologists. In the event of a disparate reading, a third gynecologic pathologist evaluated the tissue using predetermined criteria. RESULTS: Endometrial hyperplasia was found in 37.9% (39 of 103) in the E2 alone group versus 0.8% (one of 123), 1% (one of 98), and 1.1% (one of 89) in the E2-norethindrone acetate 50-140, 50-250, and 50-400 groups, respectively (P < .001). Uterine bleeding was less frequent in the E2-norethindrone acetate 50-140 group than other treatments. The mean number of hot flushes per day decreased to less than one in each treatment group at endpoint. The E2-norethindrone acetate combination patch showed skin tolerance comparable to that of E2 alone. CONCLUSION: Continuous transdermal delivery of E2 combined with norethindrone acetate effectively prevented endometrial hyperplasia in healthy postmenopausal women. Continuous combined transdermal delivery systems provide increased dosing flexibility and might improve convenience and compliance with hormone replacement therapy.

A dose-ranging trial of a matrix transdermal 17beta-estradiol for the prevention of bone loss in early postmenopausal women. International Study Group.

This international, randomized, double-blind, placebo-controlled, parallel group, dose-ranging trial was designed to determine the efficacy of 2 years of therapy with a new matrix transdermal 17beta-estradiol (Menorest) in preventing bone loss in early postmenopausal women, and to identify an appropriate dose. Two hundred ninety-two ambulatory women with natural or surgical menopause for 1-6 years were randomized to receive patches delivering 17beta-estradiol 50, 75, or 100 microg/day twice weekly for 25 days per 28 day cycle (with dydrogesterone 10 mg twice daily from days 11 to 24) or placebo, for 24 months. The primary outcome measure was the percentage change from baseline in lumbar spine bone mineral density (BMD) at 2 years. Secondary endpoints were percentage changes from baseline in three sites of proximal femur BMD and total body BMD, and in biochemical bone turnover markers. At 2 years, the difference from placebo in percentage change from baseline of L1-4 spine BMD was 6.2%, 7.6%, and 7.8% in the 50, 75, and 100 microg/day groups, respectively. Lumbar spine bone increased in 65.5%, 76.8%, and 81.0% of patients in the respective active treatment groups, compared with 4.9% on placebo. BMD increased significantly relative to placebo in the femoral neck, trochanter, total hip, and total body. Serum osteocalcin, bone alkaline phosphatase and urinary type I collagen C-telopeptide decreased significantly and dose dependently in 17beta-estradiol patients vs. placebo. For example, at 2 years, the difference between placebo and the 50 microg/day group, expressed in percentage change from baseline, was 3.25% at the femoral neck, 3.92% at the trochanter, 3.52% for total hip, and 2.40% for the total body. Breast pain and skin reactions were more common in the actively treated groups, but tolerability was generally good. Therefore, after 2 years, 17beta-estradiol was well-tolerated and highly effective at doses of between 50 and 100 microg/day in preventing bone loss and reducing bone turnover in early postmenopausal women. The dose of 50 microg/day, the lowest dose tested, is a suitable dose. There was little clinical benefit of increasing the dosage from 75 to 100 microg/day.

Efficacy and safety of Menorest (50 mikrog/day) compared to Premarin 0.625 mg in the treatment of menopausal symptoms and the prevention of bone loss, in menopausal women. A single-center, comparative, randomized, double-blind, double-dummy study.

Thirty-two (32) menopausal women were entered into the study (16 in each treatment group), of whom 24 completed the study. The objectives were to compare the long-term efficacy and the local and systemic tolerance of Menorest and Premarin in the control of menopausal symptoms, and the prevention of bone loss. After a 4-week treatment-free run-in period, patients were treated with continuous estrogen therapy (a twice weekly application with Menorest 50 or a daily oral administration of Premarin 0.625 mg) for one year. Patients were also given 20 mg oral Dydrogesterone per day for the last 12 days of each 28 day cycle of treatment. The main efficacy criterion was the reduction in the mean number of hot flushes per day at 12 months compared to baseline. This study was also considered as a pilot study to collect data on changes in the bone mineral density of the lumbar spine (L1-L4) assessments from baseline to week 30 and week 56. Menorest and Premarin were equally effective in the relief of menopausal symptoms over the 1-year period of treatment. The mean number of hot flushes per day decreased from 6.9 at baseline to 0.5 at 12 weeks and 0.1 at 12 months in the Menorest group, and from 7.0 to 0.3 and 0.0 in the Premarin group. Regarding the lumbar spine and hip densitometry results, Menorest prevented bone loss to the same extent as Premarin. This data confirms the positive action of estrogen, with oral in addition to transdermal administration on both trabecular and cortical BMD over 1 year of treatment. Tolerance was similar, with approximately the same number of patients with AEs, severe AEs and related to study drug AEs in both groups. There was one serious AE (breast carcinoma) diagnosed after 6-months of treatment. Chemotherapy and radiotherapy was initiated prior to surgery. According to the investigator it was not related to study drug and must have been present prior to study start. Menorest 50 and Premarin 0.625 were equally effective over the 1-year treatment period in reducing the mean number of hot flushes and the severity score of menopausal symptoms, including vasomotor, psychological and urogenital symptoms.

Efficacy and tolerability of Menorest 50 compared with Estraderm TTS 50 in the treatment of postmenopausal symptoms. A randomized, multicenter, parallel group study.

Two-hundred and five (205) menopausal women with moderate to severe vasomotor symptoms, aged 39-64 years, were randomized from 20 clinical centers. After a 4-week treatment-free period, each woman received a cyclical regimen (25 days of a 4-week cycle) of Menorest 50, a new matrix-type transdermal estradiol system or Estraderm TTS 50, a marketed reservoir-type transdermal estradiol system twice weekly for 12 weeks. An oral progestin was also given for 10 days each cycle. The objectives were to compare local and systemic tolerability and efficacy in the treatment of menopausal symptoms. One-hundred and ninety-four [194] patients (96 and 98 patients in the Menorest 50 and the reservoir transdermal patch groups, respectively) were considered in the intent-to-treat population and 204 (102 in each group) in the safety population. The two treatment groups were comparable with regard to the demographic data and menopausal status. The primary efficacy criteria were the comparison between Menorest 50 and the reservoir transdermal patch in erythema and pruritus at application sites and the difference between the treatment groups in the mean number of hot flushes per day at week 12, adjusted for baseline. A statistically significant reduction in the mean number of hot flushes was observed in each group compared with baseline, with a decrease from 6.5 at baseline to 0.3 at 12 weeks and 6.4 to 0.4 in the Menorest 50 and reservoir transdermal patch groups respectively; there was no statistically significant difference between the two groups during the 12-week treatment. The severity score of menopausal symptoms was also dramatically improved in each of the two treatment groups. There were no statistically significant differences in the mean plasma estradiol concentrations and mean estradiol to estrone ratio (> 1.0) in both groups after 10 weeks of therapy. A similar number of adverse events was observed in both groups. Menorest 50 showed better local tolerability than the reservoir transdermal patch with a lower incidence of topical adverse events, erythema and pruritus. In summary, Menorest 50 was as effective as the reservoir transdermal patch in reducing the mean number of hot flushes, and improving the severity of other menopausal symptoms, including vasomotor, psychiatric and urogenital symptoms.

Efficacy and tolerance of Menorest compared to Premarin in the treatment of postmenopausal women. A randomised, multicentre, double-blind, double-dummy study.

Two-hundred and fourteen (214) menopausal women with moderate to severe vasomotor symptoms, aged 40-65 years, were randomised. After a 4-week treatment-free period, each women received a continuous regimen of Menorest 50 twice weekly or Premarin 0.625 mg daily, for 12 weeks. Didrogesterone 10 mg was also given to all women for 12 days of every 28-day cycle. The objectives were to compare the efficacy and safety profiles of Menorest and an oral estrogen. A statistically significant reduction in the mean number of hot flushes occurred in each group compared to baseline with a decrease from 7.1 at baseline to 0.9 at 12 weeks in the Menorest group, and from 6.7 to 0.5 in the oral estrogen group; there was no statistically significant difference between the two groups (P = 0.36). With each successive treatment cycle, there was a continuous improvement in the number of hot flushes. The incidence and severity of menopausal symptoms were reduced in the same manner in both groups. There were no statistically significant differences in the mean plasma estradiol and estrone concentrations between the two treatment groups after 10 weeks of therapy. The mean estradiol to estrone ratio was similar in both groups, as was the number of adverse events observed. In summary, Menorest was as effective as an oral estrogen in alleviating menopausal symptoms.

Bioavailability Study of Menorest®, a New Estrogen Transdermal Delivery System, Compared with a Transdermal Reservoir System.

The aim of this study was to compare the bioavailability and plasma profiles of estradiol and estrone after repeated applications of 2 types of estradiol transdermal systems: a new adhesive matrix system (Menorest®) compared with a reference membrane/reservoir system (Estraderm®) and to evaluate their short term safety. This was an open, randomised, crossover study, with 2 treatment periods of 10.5 days separated by a 10-day washout period and with a 1-week follow-up. Participants were studied at Institut Aster, Paris, and Association de Recherche Thérapeutique (ART), Lyon, France, and included 31 healthy postmenopausal women, all volunteers aged between 49 and 67 years (mean 58 years). Each transdermal system was applied for three successive 3.5 day-wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, before and after the third application of each transdermal system at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. Although the extent of availability [area under the plasma concentration-time curve (AUC) and average plasma concentration (Cav)] was similar with both transdermal systems, their pharmacokinetic profiles were different, with Menorest® producing less fluctuating and more sustained plasma estradiol levels than the reference system. The mean estradiol to estrone Cav ratio was similar with the 2 transdermal systems and in the physiological range of premenopausal status. The incidence of adverse events was similar for both treatments, but a lower incidence of local erythema was observed with Menorest® (8.9%) than with the reference system (18.3%). In conclusion, during the entire wear period, Menorest® produced more sustained plasma estradiol levels with less fluctuations (40 to 72 ng/L) than the reservoir/ membrane system (18 to 102 ng/L). Menorest® gave estradiol plasma levels approximating the concentrations observed during the early to mid-follicular premenopausal stage, with a 2-fold lower incidence of erythema than with the reservoir/membrane system.

Clinical evaluation of a new triphasic oral contraceptive: norgestimate and ethinyl estradiol.

The safety and efficacy of the triphasic oral contraceptive agent containing norgestimate and ethinyl estradiol were evaluated in a 12-month study of 661 women. Excellent contraceptive efficacy was achieved, with two pregnancies ascribed to product failure in a total of 6,511 treatment cycles. The life-table predicted pregnancy rate was 0.57 per 100 woman-years of use. The overall and theoretical Pearl indexes were 0.55 and 0.37, respectively. Good cycle control was maintained in patterns similar to those noted in previous studies. The incidence of dysmenorrhea and premenstrual syndrome was sharply reduced. Side effects reported were typical of those associated with use of low-dose oral contraceptive agents. Acceptability was high compared with agents used previously by the subjects. Total cholesterol did not change but high-density lipoprotein cholesterol was significantly elevated at 3 and 12 months. There were no clinically significant changes in the parameters of hematology or blood chemistry tested.

PIP: The safety and efficacy of the triphasic oral contraceptive (OC) containing norgestimate and ethinyl estradiol were evaluated in a 12-month study of 661 women. Excellent contraceptive efficacy was achieved, with 2 pregnancies ascribed to product failure in a total of 6511 treatment cycles. The life-table predicted pregnancy rate was 0.57/100 woman-years of use. The overall and theoretical Pearl indexes were 0.55 and 0.37, respectively. Good cycle control was maintained in patterns similar to those noted in previous studies. The incidence of dysmenorrhea and premenstrual syndrome was sharply reduced. Those side effects reported were typical of those associated with use of low-dose OCs. Acceptability was high compared with OCs used previously by these subjects. Total cholesterol did not change but high-density lipoprotein cholesterol was significantly elevated at 3 and 12 months. There were no clinically significant changes in the parameters of hematology or blood chemistry tested.

A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations containing norgestimate or levonorgestrel.

The effects of norgestimate triphasic (Ortho Tri-Cyclen, Tri-Ciles) and levonorgestrel triphasic (Triphasi) formulations on lipid and androgen metabolism were assessed in a study of 66 healthy women treated through six menstrual cycles. Levels of the following were measured: cholesterol and its subfractions, triglycerides, carrier lipoproteins, estradiol, testosterone, and sex hormone binding globulin (SHBG). Comparison of baseline values with values after 3 and 6 months of treatment indicated that both regimens influenced lipid and androgen metabolism. There was a statistically significant between-regimen difference in levels of high-density lipoprotein, which were favorably increased with norgestimate triphasic but reduced with levonorgestrel triphasic. Related data on SHBG showed that plasma levels of this marker of estrogen/androgen balance were increased significantly more in the norgestimate triphasic group, providing additional evidence of low androgenicity. Both regimens inhibited follicular growth to the same extent, as evidenced by low mean levels of estradiol in all on-therapy cycles; and both decreased free testosterone. Side effects in both groups were minor and characteristic of those observed with low-dose oral contraceptive agents. The results of the study support the reported safety and positive effects of norgestimate on lipid and androgen metabolism, in comparison with a levonorgestrel-containing combined oral contraceptive.

PIP: The effects of norgestimate triphasic (Ortho Tri-Cyclen, Tri-Cilest) and levonorgestrel triphasic (Triphasil) formulations on lipid and androgen metabolism were assessed in a study of 66 healthy women who were treated through 6 menstrual cycles. Levels of the following were measured: cholesterol and its subfractions, triglycerides, carrier lipoproteins, estradiol, testosterone, and sex hormone binding globulin (SHBG). Comparison of baseline values after 3 and 6 months of treatment indicated that both regimens influenced lipid and androgen metabolism. There was a statistically significant between-regimen difference in the levels of high-density lipoprotein, which increased favorably with norgestimate triphasic but were reduced with levonorgestrel triphasic. Related data on SHBG showed that plasma levels of this marker of estrogen/androgen balance were increased significantly more in the norgestimate triphasic group, providing additional evidence of low androgenicity. Both regimens inhibited follicular growth to the same extent, as seen by low mean levels of estradiol in all of the on-therapy cycles. Both decreased free testosterone. Side effects in both groups were minor and characteristic of those observed with low-dose oral contraceptives (OCs). The results of the study support the reported safety and positive effects of norgestimate on lipid and androgen metabolism, in comparison with a levonorgestrel-containing combined OC.