Transient nausea and, to a lesser extent, vomiting are common adverse effects of exenatide that can be mitigated by dose titration and usually do not result in treatment discontinuation. This retrospective analysis of data from a phase 1, open-label, parallel-group, single-dose study in healthy subjects evaluated the effect of oral anti-emetics on exenatide-associated nausea and vomiting and on the pharmacokinetics of exenatide.
A single subcutaneous dose (10 μg) of exenatide was administered to 120 healthy subjects (19–65 years, BMI 23–35 kg/m2). Incidences of nausea and vomiting were compared between 60 subjects premedicated with two oral anti-emetics 30 min before the exenatide dose and 60 non-premedicated subjects. Similarly, the area under the concentration-time curve (AUC) and the maximum observed concentration (Cmax) of plasma exenatide concentrations over 8 h post-dose were compared.
Among all subjects [61% male, 32 ± 12 years, body mass index (BMI) 29.1 ± 3.4 kg/m2 (mean ± sd)], mild to moderate nausea was the most frequent adverse event after exenatide dosing. Vomiting was also observed. Subjects premedicated with anti-emetics experienced significantly less nausea and vomiting (16.7 and 6.7%, respectively) vs. non-premedicated subjects (61.7 and 38.3%, respectively; P-value < 0.0001 for both nausea and vomiting). The mean area under the concentration-time curve and the maximum observed concentration AUC and Cmax of plasma exenatide concentrations during 8 h post-dose were not significantly different between groups.
Administration of oral anti-emetics before a single 10-μg exenatide dose was associated with significant reductions in treatment-emergent nausea and vomiting, with no discernible effect on the pharmacokinetics of exenatide. Use of anti-emetic therapy may provide a short-term strategy to minimize the nausea and vomiting associated with exenatide treatment.
anti-emetics; exenatide; nausea; vomiting
In the initial 26-week, double-blind, double-dummy assessment period of the DURATION-2 trial in patients with Type 2 diabetes on metformin, the once-weekly glucagon-like peptide 1 (GLP-1) receptor agonist exenatide once-weekly resulted in greater HbA1c improvement and weight reduction compared with maximum approved daily doses of sitagliptin or pioglitazone. This subsequent, 26-week, open-label, uncontrolled assessment period evaluated the safety and efficacy of (i) continued exenatide once-weekly treatment and (ii) switching from sitagliptin or pioglitazone to exenatide once-weekly.
Randomised oral medications were discontinued and all patients received exenatide once-weekly. Of the 364 patients [original baseline HbA1c 8.5 ± 1.1% (70 mmol/mol), fasting plasma glucose 9.0 ± 2.5 mmol/l, weight 88 ± 20 kg) who continued into the open-label period, 319 patients (88%) completed 52 weeks.
Evaluable patients who received only exenatide once-weekly demonstrated significant 52-week improvements (least square mean ± se) in HbA1c (−1.6 ± 0.1%), fasting plasma glucose (−1.8 ± 0.3 mmol/l) and weight (−1.8 ± 0.5 kg). Evaluable patients who switched from sitagliptin to exenatide once-weekly demonstrated significant incremental improvements in HbA1c (−0.3 ± 0.1%), fasting plasma glucose (−0.7 ± 0.2 mmol/l) and weight (−1.1 ± 0.3 kg). Patients who switched from pioglitazone to exenatide once-weekly maintained HbA1c and fasting plasma glucose improvements (week 52: −1.6 ± 0.1%, −1.7 ± 0.3 mmol/l), with significant weight reduction (−3.0 ± 0.3 kg). Exenatide once-weekly was generally well tolerated and adverse events were predominantly mild or moderate in intensity. Nausea was the most frequent adverse event in this assessment period (intent-to-treat: exenatide once-weekly-only 5%; sitagliptin → exenatide once-weekly 11%; pioglitazone → exenatide once-weekly 10%). No major hypoglycaemia was observed.
Patients who switched to once-weekly exenatide from daily sitagliptin or pioglitazone had improved or sustained glycaemic control, with weight loss.
exenatide; glucagon-like peptide 1; pioglitazone; sitagliptin; Type 2 diabetes
Several antibiotics have been reported to lessen the ovarian suppression produced by oral contraceptive agents, as a result of drug interactions. The present investigation was designed to study the likelihood of the occurrence of any such interaction between the fluoroquinolone antibiotic ciprofloxacin (Ciproxin) at a dosage of 500 mg twice a day and the “low-dose” oral contraceptive Marvelon (30 μg of ethinyl estradiol [EE] plus 150 μg of desogestrel). Twenty-four healthy female volunteers were studied in a double-blind, placebo-controlled, randomized crossover trial. There were no significant differences between measurements of the area under the concentration-time curve of EE up to 24 h after oral contraceptive intake during placebo and ciprofloxacin administration on days 11 and 16 of the cycles, indicating the absence of pharmacokinetic interaction. Similarly, no clinically significant differences in the levels of sex hormone binding globulin were found between the placebo and ciprofloxacin cycles, indicating no major variation in EE levels during ciprofloxacin and placebo treatment. Ten subjects in each of the placebo and ciprofloxacin groups had early-follicular-phase levels of 17-β estradiol (<184 ng/liter) at one or more points during their cycles, but none had values above the early-follicular-phase range, indicating no significant ovarian activity. In addition, all subjects had progesterone levels of <2 ng/ml, indicating the absence of ovulation. Only two subjects, who received the placebo, had evidence of sustained follicular growth to a potentially ovulatory follicle (∼18 mm). We conclude that ciprofloxacin does not interfere with the ovarian suppression produced by the low-dose oral contraceptive Marvelon.
Exenatide improves postprandial glycemic excursions in type 2 diabetes. Exenatide could benefit type 1 diabetes as well. We aimed to determine an effective and safe glucose-lowering adjuvant exenatide dose in adolescents with type 1 diabetes.
RESEARCH DESIGN AND METHODS
Eight subjects completed a three-part double-blinded randomized controlled study of premeal exenatide. Two doses of exenatide (1.25 and 2.5 μg) were compared with insulin monotherapy. Prandial insulin dose was reduced by 20%. Gastric emptying and hormones were analyzed for 300 min postmeal.
Treatment with both doses of exenatide versus insulin monotherapy significantly reduced glucose excursions over 300 min (P < 0.0001). Exenatide administration failed to suppress glucagon but delayed gastric emptying (P < 0.004).
Adjunctive exenatide therapy reduces postprandial hyperglycemia in adolescents with type 1 diabetes. This reduction in glucose excursion occurs despite reduction in insulin dose. We suggest that exenatide has therapeutic potential as adjunctive therapy in type 1 diabetes.
To compare the effects of two monophasic combined oral contraceptives, containing either nomegestrol acetate/17β-oestradiol (NOMAC/E2) or levonorgestrel/ ethinylestradiol (LNG/EE) on endocrine function, androgens, and sex hormone-binding globulin (SHBG).
Randomised, open-label, multi-centre trial involving 121 healthy women, aged 18-50 years old. Participants received NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n = 60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n = 61) for six cycles. The primary outcome was the change from baseline to cycle 6 in markers of adrenal and thyroid function, androgens, and SHBG.
Total cortisol, corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG) increased from baseline in both groups, with significantly greater increases in the LNG/EE group. No relevant changes from baseline or differences between the groups were observed for thyroid-stimulating hormone (TSH) and free thyroxine (T4). Androgens and androgen precursors decreased from baseline in both groups, with significantly greater decreases in the LNG/EE group (except for free testosterone). A greater increase in SHBG was observed with NOMAC/E2 than with LNG/EE.
NOMAC/E2 has significantly less influence on markers of adrenal and thyroid function and androgens than LNG/EE. The clinical relevance of these findings requires further study.
Oral contraceptives; Nomegestrol acetate; 17β-oestradiol; Adrenal; Thyroid; Androgen; SHBG
Extended-cycle oral contraceptives (OCs) are increasing in popularity in the United States. A new extended-cycle OC that contains the lowest doses of ethinyl estradiol (EE) and levonorgestrel (LNG) + continuous EE throughout the cycle is now available. It provides 84 days of a low-dose, combined active pill containing levonorgestrel 100 μg and ethinyl estradiol 20 μg. Instead of 7 days of placebo following the active pills, the regimen delivers 7 days of ethinyl estradiol 10 μg. Existing studies reveal a similar efficacy and adverse effect profile compared with other extended-regimen OCs. Specifically, the unscheduled bleeding profile is similar to other extended-cycle OCs and improves with the increase in the duration of use. Although lower daily doses of hormonal exposure have potential benefit, to our knowledge, there are no published studies indicating that this specific regimen offers a lower incidence of hormone-related side effects or adverse events. In summary, this new extended-cycle OC provides patients a low-dose, extended-regimen OC option without sacrificing efficacy or tolerability.
continuous regimen; ethinyl estradiol; extended cycle; oral contraceptive
Objectives. Compare the Plan B levonorgestrel (LNG) area under the concentration- time curve (AUC12) prior to and with efavirenz (EFV). Design. Prospective, open-label, single-arm, equivalence study. Methods. Healthy HIV-negative subjects underwent 12 hr intensive pharmacokinetic (PK) sampling following single dose LNG alone and after 14 days of EFV. Geometric means, Geometric Mean Ratios, and 90% confidence intervals (CI) are reported for PK Parameters. T-tests were utilized. Clinical parameters and liver function tests (LFTs) were assessed. Results. 24 women enrolled and 21 completed the study. With EFV, LNG AUC12 was reduced 56% (95% CI: 49%, 62%) from 42.9 to 17.8 ng∗hr/mL, and maximum concentration (Cmax) was reduced 41% (95% CI: 33%, 50%) from 8.4 to 4.6 ng/mL. LNG was well tolerated with no grade 3 or 4 treatment-related toxicities. Conclusions. EFV significantly reduced LNG exposures. Higher LNG doses may be required with EFV. These results reinforce the importance of effective contraception in women taking EFV.
The progestational steroid norgestrel was synthesized and tested between 1960 and 1965 through an international cooperation between Wyeth, USA and Schering, Berlin. It is a mixture of two “enantiomers,” with only one form (designated as levonorgestrel) biologically active. When taken orally, it is rapidly absorbed, not subjected to a “first-pass” effect and is approximately 90% bioavailable, with a circulating half-life around 15 hours. Its contraceptive action is exerted at the central (hypothalamic) and peripheral (cervical mucus and endometrium) levels. Levonorgestrel (LNG), alone or in combination with ethinyl estradiol (EE), is the most widely employed contraceptive progestin: it is used in combined oral contraceptives, progestogen-only pills, long-acting contraceptive implants, intrauterine contraceptive systems and in emergency contraception. It is also the steroid of choice for new oral contraceptive regimens aimed at reducing the frequency of bleeding episodes. This novel approach, already tried more than 30 years ago, gained interest around the year 2000 when surveys of women’s attitudes toward monthly menstrual bleeding started to show a major change: more and more women declared that they would welcome a hormonal contraceptive method that reduced bleeding episodes to 4, 2 or even 1 per year. At this point, while the debate on the significance and “usefulness” of menstruation went on, attention focused on new regimens. The first new modality consisted of changing the 7-day medication-free interval, either shortening it to fewer than 7 days, or by the administration of low-dose estrogens during the interval between packages. Then, continuous administration regimens started to be investigated. This, however, did not happen suddenly, since, in specific situations, doctors had for years empirically utilized various continuous administration regimens. The first extended-cycle oral contraceptive regimen introduced in clinical practice is an 84-day regimen that results in bleeding only 4 times a year. A commercial product specifically packed for continuous use is now available in Europe and contains 30 μg EE and 150 μg LNG. In a variation of this regimen, after administration of the same combination for 84 days, women are given 7 pills containing 10 μg EE. A 6-monthly regimen has also been tested in a small study using EE 20 μg plus LNG 100 μg taken with and without a hormone-free interval. Women in the continuous group reported significantly fewer bleeding days requiring protection and were more likely to have amenorrhea; in addition they also reported significantly fewer days of bloating and menstrual pain. A yearly regimen is now being developed. Each pill of this novel formulation contains EE 20 μg and LNG 90 μg to be taken continuously for 364 days (13 cycles) per year. A phase III trial has now evaluated safety, efficacy and menses inhibition. At the end of the 1-year trial amenorrhea was present in 58.7% of the women and a complete absence of bleeding in 79.0%. Overall, the number of bleeding and spotting days per pill pack declined with time and adverse events and discontinuations were comparable to those reported for cyclic oral contraceptive regimens.
levonorgestrel; oral contraceptive; continuous administration; menstruation; amenorrhea
To compare the effects of a combined oral contraceptive (COC) containing nomegestrol acetate and 17β-oestradiol (NOMAC/E2) on haemostasis, lipids, carbohydrate metabolism, C-reactive protein (CRP) and sex hormone-binding globulin (SHBG) with those of a COC containing levonorgestrel and ethinylestradiol (LNG/EE).
In a randomised, open-label study, 121 healthy women, 18-50 years of age, were randomly assigned to receive NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n = 60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n = 61) for six cycles. The primary outcome was the change from baseline to cycle 6 for all indices.
All parameters were similar at baseline between the two groups. Over six cycles, NOMAC/E2 had less effect on most haemostatic indices than LNG/EE. Lipids were essentially unchanged with NOMAC/E2, whereas with LNG/EE high-density lipoprotein cholesterol decreased and low-density lipoprotein cholesterol and triglycerides slightly increased. NOMAC/E2 induced negligible changes in glucose and insulin parameters, in contrast to LNG/EE. A much smaller increase in CRP was observed with NOMAC/E2 than with LNG/EE. NOMAC/E2 was associated with a greater increase in SHBG.
The monophasic COC NOMAC/E2 had less influence on haemostasis, lipids and carbohydrate metabolism than the COC LNG/EE.
Oral contraceptives; Nomegestrol acetate; Oestradiol; Haemostasis; Lipids; Carbohydrates
This study was conducted to compare ovarian suppression during oral versus vaginal hormonal contraceptive use. Secondary aims included comparison of endometrial thickness and bleeding patterns.
In two open-label trials assessing ovarian suppression, 33 compliant women completed both studies. They first used OCs [randomized to either 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) or 30 mcg EE/150 mcg LNG] and subsequently used contraceptive vaginal rings (CVR) (daily release of 15 mcg EE/120 mcg etonogestrel), all 21/7 day regimens. Participants had at least one run-in cycle using each contraceptive method prior to evaluation. During one cycle of each method, women underwent bi-weekly transvaginal sonography to measure ovarian follicular diameters and endometrial thickness. We also noted presence of a corpus luteum or a ruptured follicle as a marker of ovulation. Participants recorded bleeding days on paper calendars. We used matched pairs analyses as appropriate.
During follow-up, we identified at least one ovarian follicle ≥8 mm in 20/33 (61%) OC users and 12/33 (36%) CVR users (matched pairs analysis, p=0.02). Similar trends were seen for larger follicles; however we had limited statistical power to evaluate these differences. Median follicular diameter among OC users was larger than median follicular diameter among CVR users (p=0.01). We did not observe a corpus luteum or ruptured follicle in any participant during either study. Endometrial thickness was similar during OC and CVR use (mean 4.1 ± 1.4 mm versus 4.1 ± 1.6 mm, p=0.9) as was the number of bleeding or spotting days (mean 2.1 ± 2.4 versus 1.9 ± 2.1, p=0.8). OC dose was unrelated to follicle diameter, endometrial thickness, or bleeding.
Ovarian follicles ≥8 mm were more common in 33 compliant women during OC use than during CVR use indicating CVR use results in greater ovarian suppression than OC use.
NuvaRing®; Oral Contraception; Ovarian Suppression
Exenatide is an incretin mimetic that is recently available in the US for the treatment of diabetes. There is a paucity of information on the effects of exenatide in glucocorticoid (GC)-induced diabetes. Although the effect of continuous intravenous infusion of exenatide on GC-induced glucose intolerance has been investigated before in healthy human males receiving oral prednisolone, we investigated the efficacy of a single subcutaneous dose of exenatide (3 μg/kg) in lowering blood glucose in GC-induced glucose intolerance in C57BL/6 mice. In a longitudinal experiment, the area under the curve (AUC) of oral glucose tolerance tests (OGTT) significantly increased after dexamethasone (P = 0.004), which was subsequently decreased by exenatide (P < 0.001). A cross-sectional experiment showed that exenatide improved glucose tolerance compared with placebo in a mouse model of dexamethasone-induced glucose intolerance. AUC of OGTT in the exenatide group were significantly (P < 0.001) lower than in the placebo group. Insulin tolerance tests (ITT) demonstrated that exenatide decreased the ability of the mice to tolerate insulin compared with placebo. The AUC of ITT in the exenatide group were also significantly (P = 0.006) lower than in the placebo group. In conclusion, a single dose of exenatide was able to decrease glucose intolerance and insulin resistance in these placebo-controlled experiments. Future clinical trials are justified to investigate the role of exenatide in the treatment of GC-induced glucose intolerance/diabetes.
exenatide; dexamethasone; glucocorticoid; insulin resistance; mouse model
Menstrual disturbances in female athletes are often explained as a consequence of energy deficiency. Oral contraceptive (OC) treatment may have favorable metabolic effects. We evaluated effects of OCs on diurnal secretions of insulin, insulin-like growth factor binding protein 1 (IGFBP-1), growth hormone (GH) and cortisol in relation to changes in body composition in athletes with menstrual disturbance compared with regularly menstruating athletes and controls.
Age- and BMI-matched groups of endurance athletes with menstrual disturbance (OAM, n = 9) and regularly cycling athletes (RM, n = 8) and sedentary controls (CTRL, n = 8) were examined, and hormone levels measured, before and after 8 months of treatment with a low-dose combined OC (30 µg ethinyl estradiol + 150 µg levonorgestrel).
Before OC treatment, the diurnal profile of insulin was lower (P < 0.01) and levels of IGFBP-1 (P < 0.05) and cortisol (P < 0.05) were higher in OAM athletes than in CTRL, whereas GH secretion was higher than in RM athletes (P < 0.05). After treatment, diurnal secretions of these hormones were similar between groups with an increase of IGFBP-1 in the regularly menstruating subjects only (P < 0.001). OC treatment increased body fat mass in OAM athletes (P < 0.01 versus baseline). The change in total fat mass correlated positively with pretreatment diurnal levels of GH (rs = 0.67, P < 0.01) and cortisol (rs = 0.64, P < 0.01).
OC treatment in endurance athletes with menstrual disturbance increases body fat mass and results in diurnal levels of insulin, IGFBP-1, GH and cortisol that are comparable to those in regularly menstruating subjects. These results suggest that OCs improve metabolic balance in OAM athletes.
oral contraceptives; female athletes; menstrual disturbances; insulin-like growth factor binding protein 1; body fat
Background: A novel estradiol-based combined oral contraceptive (COC) is currently available in many countries worldwide, including Europe and the US. Based on previous studies, it is expected that this estradiol-based COC will have a reduced hepatic effect compared with COCs containing ethinylestradiol with regard to proteins controlling the hemostatic balance.
Objective: The aim of this study was to compare the hemostatic effects of the estradiol valerate/dienogest COC with a monophasic low-estrogen dose COC containing ethinylestradiol/levonorgestrel.
Study Design: Healthy women aged 18–50 years were randomized to receive a COC containing estradiol valerate/dienogest (2 days estradiol valerate 3 mg, 5 days estradiol valerate 2mg/dienogest 2 mg, 17 days estradiol valerate 2mg/dienogest 3 mg, 2 days estradiol valerate 1 mg, 2 days placebo) or ethinylestradiol 0.03mg/levonorgestrel 0.15mg in a crossover study design. Women received each treatment for three cycles, with two washout cycles between treatments. The primary efficacy variables were the intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three.
Results: Data from 29 women were assessed. Intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three were less pronounced with estradiol valerate/dienogest than with ethinylestradiol/ levonorgestrel.
Conclusion: The novel COC containing estradiol valerate/dienogest had similar or less pronounced effects on hemostatic parameters than ethinylestradiol/ levonorgestrel.
Anti-epileptic drugs (AEDs) are widely used in reproductive-age women. The AED carbamazepine (CBZ) induces the hepatic cytochrome p450 system accelerating hormone metabolism. We sought to assess the pharmacodynamic effects of CBZ on breakthrough bleeding and ovulation during OC use.
A double-blind, randomized, cross-over study of healthy women ages 18 to 35 years. Participants took an OC containing 20 mcgs ethinyl estradiol (EE) and 100 mcgs levonorgestrel (LNG) for four months. Concurrently, participants took CBZ 600 mgs or a matching placebo for two months each, administered in random order. During the second month of CBZ or placebo, we measured EE and LNG levels twelve times over 24 hours, ovarian follicular diameters with eight bi-weekly vaginal ultrasounds, weekly progesterone levels and bleeding using a diary.
We enrolled 25 women; 10 completed the study. Five discontinued due to reversible CBZ side effects. Mean area under the curve measurements were lower during CBZ use compared to placebo for EE (1778 versus 986 pg*h/ml, p<0.001) and LNG (24.8 vs. 13.8 pg*h/ml, p=0.04). Ovulation occurred in 5 of 10 CBZ cycles compared to 1 of 10 placebo cycles (p=0.06). Three or more days of breakthrough bleeding occurred during 8 of the 10 CBZ cycles compared to 2 of the 10 placebo cycles (p= 0.07).
A commonly used dose of CBZ decreased levels of contraceptive steroids, increased breakthrough bleeding and permitted ovulation during use of a low-dose OC. Women treated with CBZ are not adequately protected from pregnancy by low-dose OCs.
anti-epileptic drugs; contraception; oral contraceptives; carbamazepine
To assess treatment satisfaction and weight-related quality of life (QOL) in subjects with Type 2 diabetes treated with exenatide once weekly (QW) or twice daily (BID).
In this 52-week randomized, multi-centre, open-label study, 295 subjects managed with diet and exercise and/or oral glucose-lowering medications received either exenatide QW or BID during weeks 1–30; thereafter, subjects receiving exenatide BID were switched to exenatide QW, with 258 total subjects receiving exenatide QW during weeks 30–52. Diabetes Treatment Satisfaction Questionnaire—status (DTSQ-s) and Impact of Weight on Quality of Life—Lite (IWQOL-Lite) were assessed at baseline and weeks 30 and 52. Mean group changes from baseline to week 30 were estimated by ancova; changes from week 30 to week 52 were assessed by Student’s t-test.
Statistically significant improvements from baseline to week 30 were observed in both treatment groups for DTSQ-s and IWQOL-Lite measures, with significantly greater reduction in perceived frequency of hyperglycaemia and greater satisfaction with continuing treatment in the QW group compared with the BID group. Effect sizes for change in DTSQ-s total scores were 0.84 QW, 0.64 BID; for IWQOL-Lite: 0.96 QW, 0.82 BID. Treatment satisfaction and QOL improved significantly between weeks 30 and 52 for those switching from BID to QW. Occurrence of adverse events did not affect patients’ improvements in treatment satisfaction and QOL.
Patients treated with exenatide QW or BID experienced significant and clinically meaningful improvements in treatment satisfaction and QOL. Patients who switched from exenatide BID to exenatide QW administration reported further significant improvements.
exenatide; treatment satisfaction; Type 2 diabetes mellitus
Data on 2,754 cases and 18,565 controls from a multinational hospital-based, case-control study were analysed to determine whether observed associations between combined oral contraceptives and breast cancer are similar for oral contraceptives with varying types and doses of oestrogens and progestins. After stratifying on duration of use, risk was found to be increased in current and recent users, and to decline with time since last use. These associations, of similar strength, were observed for users of products that contain mestranol and ethinyl estradiol, for women who used preparations with progestins derived from 19-nortestosterone and 17-alpha-hydroxyprogesterone, and for those who took preparations with relatively higher and lower doses of oestrogen. When products with equal doses of the same oestrogen or progestin and varying doses of the other hormonal constituent were considered, slightly higher relative risks per year of use were estimated for users of products with relatively higher than lower doses of either the constituent oestrogen or progestin, but the differences in relative risk could readily have occurred by chance. This study provides no evidence that risk of breast cancer in users of oral contraceptives varies by the type of oestrogen or progestin consumed.
This study was conducted to determine whether increased body mass index (BMI) affects oral contraceptive (OC) pharmacokinetics and suppression of hypothalamic-pituitary-ovarian (HPO) axis activity.
Ovulatory reproductive-age women of normal (< 25 kg/m2; n = 10) and obese (> 30 kg/m2; n = 10) BMI received OCs for two cycles (prospective cohort). Subjects were admitted for two 48-h inpatient stays at the beginning and end of the hormone-free interval. Ethinyl estradiol (EE) and levonorgestrel (LNG) levels were evaluated during both inpatient stays. Gonadotropin pulsatility (FSH and LH) was measured during the second inpatient stay. Estradiol (E2) and progesterone (P) were measured daily during inpatient stays and twice per week in Cycle 2.
BMI was greater in the obese, compared to the normal BMI group [37.3 kg/m2 (SD 6.0) versus 21.9 kg/m2 (SD 1.6); p < 0.05]. The LNG half-life was significantly longer in the obese group (52.1 ± 29.4 h versus 25.6 ± 9.3 h, p < 0.05) which correlated with a lower maximum LNG concentration on Cycle 2, Day 1 [1.9 ng/mL (SD 0.5) versus 2.5 ng/mL (SD 0.7)] and a longer time to reach steady-state (10 versus 5 days), in obese women. There were no significant differences in volume of distribution between groups. LH pulse parameters did not differ statistically between groups but trended towards greater HPO activity in the obese group. Additionally, more obese (6/10 versus 3/10 normal BMI, p > 0.05) women exhibited E2 levels consistent with development of a dominant follicle, and P levels consistent with ovulation (2/10 versus 1/10) during Cycle 2.
Compared to women of normal BMI, obese women exhibit differences in OC pharmacokinetics that are associated with greater HPO activity.
To evaluate the effect of exenatide on gastric emptying and long-term metabolic control.
Ten islet allograft recipients treated with exenatide up to 4 years. Data from a mixed meal test with (MMT+) versus without (MMT−) administration of exenatide before boost ingestion were analyzed at 6, 12, 24, 36, or 48 months after initiation of exenatide treatment. None of the subjects were symptomatic for gastroparesis before or during the study. The c-peptide, acetaminophen absorption and glucose responses to MMT were analyzed by Student t test and analysis of variance.
Average exenatide dose was 12.75 ± 9.46 μg/dL. The MMT subjects included two groups those with acetaminophen peak ≤120 minutes (“good gastric emptying; n = 4”) versus those with an acetaminophen peak ≥180 minutes (“delayed gastric emptying”). Among the MMT+, acetaminophen absorption was the same in both groups (P = .27). Up to 48 months exenatide delayed time to peak of glucose, c-peptide, and acetaminophen as well as suppressed the glucagon response to MMT mean peak: 70.89 ± 12.45 versus 43.24 ± 4.67. The mean values of c-peptide and glucose responses to MMT were not significantly different.
Long-term exenatide administration up to 4 years was safe in islet transplant recipients, even in the presence of delayed gastric emptying. The effects of exenatide were acute and reversible when the agent was withdrawn. The main difficulty with the use of exenatide in islet transplant subjects is their poor tolerability, although the physiological effects are clearly evident even at low doses. Approximately 63% of total subjects under exenatide treatment discontinued the drug due to nausea and vomiting. The use of new GLP1 analogs with longer half lives and fewer side effects may help to attain higher GLP1 levels, therefore improving islet function and survival.
In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks.
RESEARCH DESIGN AND METHODS
In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.
Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean −2.0% [95% CI −2.1 to −1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and ≤6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.
Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.
Exenatide (also known as exendin-4) is a glucagon-like peptide-1 mimetic, which is indicated for the treatment of type 2 diabetes mellitus. The currently available formulation of this drug is a twice-daily exenatide (exenatide BID) injection that should be administered within 60 minutes of food. Once-weekly exenatide (exenatide QW) formulation is now being assessed in a clinical trial program. Exenatide QW has been shown to be the only noninsulin monotherapy to achieve glycosylated hemoglobin levels of <7% in >75% of treated patients. It has also demonstrated potential cardiovascular benefits by lowering total and low-density lipoprotein cholesterol concentrations, triglyceride levels, and both systolic and diastolic blood pressure. In addition, patients treated with exenatide QW achieved significant weight loss, which may also lead to significant cardiovascular risk reduction. Exenatide QW is associated with a lower incidence of gastrointestinal adverse effects compared with exenatide BID, and no patients treated with exenatide QW monotherapy experienced a confirmed hypoglycemic event. Exenatide QW results in 24-hour coverage with exenatide concentrations that are known to improve glycemic control and remain well tolerated in patients with type 2 diabetes mellitus. This review defines the state of play with exenatide QW by critically appraising its role in clinical practice.
GLP-1 mimetic; HbA1c; weight loss
Objective To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
Design Systematic review with meta-analyses.
Data sources Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011).
Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin.
Data extraction Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors.
Results 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference −2.9 kg, 95% confidence interval –3.6 to –2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (–3.2 kg, –4.3 to –2.1; three trials) as well as patients with diabetes (–2.8 kg, –3.4 to –2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia.
Conclusions The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI).
Exenatide (5 or 10 µg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft–Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min−1, n = 8), mild RI (51–80 ml min−1, n = 8), moderate RI (31–50 ml min−1, n = 7) or end-stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL.
Mean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h−1, respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 µg q.d.).
Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 µg) unsuitable in severe RI or ESRD.
What is already known about this subjectNonclinical studies have shown that exenatide is primarily cleared by the renal system.It was not known to what degree the clinical pharmacokinetics and tolerability would be affected by increasing renal impairment (RI).
What this study addsPatients with mild to moderate RI adequately tolerate current therapeutic doses of exenatide.However, exenatide is not recommended in patients with severe RI or end-stage renal disease.
end-stage renal disease; exenatide; incretin mimetic; pharmacokinetics; renal impairment; Type 2 diabetes
Fertile women may be encouraged to use contraception during clinical trials to avoid potential drug effects on fetuses. However, hormonal contraception interferes with pharmacokinetics and pharmacodynamics and modifies internal milieus. Macrophages depend on the milieu to which they are exposed. Therefore, we assessed whether macrophage function would be affected by the use of combined oral contraceptives (OCs) and if this influence depended on the androgenic or non-androgenic properties of progestin.
Healthy adult women were enrolled and stratified into two groups: women who did not use OCs (Fs) and women treated with OCs (FOCs). FOCs were further stratified as a function of androgenic (FOCA+) and non-androgenic (FOCA-) properties of progestins. Routine hematological, biochemical, inflammatory and endothelial dysfunction parameters were measured. Monocyte-derived macrophages (MDMs) were evaluated for the expression and activity of estrogen receptors and androgen receptors, and release of tumor necrosis factor α (TNFα) was measured from unstimulated and lipopolysaccharide-stimulated cells.
As is already known, the use of OCs changed numerous parameters: the number of lymphocytes, iron levels, total iron-binding capacity of transferrin, triglycerides, high-density lipoprotein, total cholesterol, and C-reactive protein increased, while prothrombin time and alkaline phosphatase decreased. Hormonal levels also varied: cortisol was higher in FOCs, while luteinizing hormone, follicle-stimulating hormone, and testosterone were lower in FOCs. Asymmetric dimethylarginine, an index of endothelial function, was lower in FOC than in Fs, as were cysteine and bilirubin. The androgenic properties of progestins affected the activity of OCs: in particular, white blood cell count, hemoglobin, high-density lipoprotein and calcium were higher in FOCA- than in FOCA+, whereas percentage oxygen saturation and γ-glutamyl transpeptidase were lower in FOCA- than in FOCA+. Importantly, FOCs had a lower global DNA methylation, indicating that OC may have epigenetic effects on gene expression. OC did not modify the expression of androgen receptor but increased estrogen receptor α expression, more considerably in FOCA+, and decreased estrogen receptor β, more considerably in FOCA-. Importantly, the activation state of estrogen receptor β in FOCs was decreased, while estrogen receptor α was not active in either Fs or FOCs. Unstimulated MDMs obtained from FOCs showed higher release of TNFα in comparison with Fs. After lipopolysaccharide stimulation, the release of TNFα was significantly higher in Fs than in FOCs.
OC use induced many changes in hematological and plasmatic markers, modifying hormonal levels, endothelial function, inflammation index and some redox state parameters, producing a perturbation of the internal milieu that impacted macrophagic function. In fact, different levels of estrogen receptor expression and release of TNFα were observed in macrophages derived from OC users. Some of the above activities were linked to the androgenic properties of progestin. Even though it is not known whether these effects are reversible, the results indicate that to avoid potential skewing of results only a single type of OC should be used during a single clinical trial.
androgenic and non-androgenic progestin; combined oral contraceptive; estrogen receptors; global DNA methylation; monocyte-derived macrophages; TNFα
Exenatide belongs to a new therapeutic class in the treatment of diabetes (incretin mimetics), allowing glucose-dependent glycaemic control in Type 2 diabetes. Randomised controlled trial data suggest that exenatide is as effective as insulin glargine at reducing HbA1c in combination therapy with metformin and sulphonylureas; with reduced weight but higher incidence of adverse gastrointestinal events. The objective of this study is to evaluate the cost effectiveness of exenatide versus insulin glargine using RCT data and a previously published model of Type 2 diabetes disease progression that is based on the United Kingdom Prospective Diabetes Study; the perspective of the health-payer of the United Kingdom National Health Service.
The study used a discrete event simulation model designed to forecast the costs and health outcome of a cohort of 1,000 subjects aged over 40 years with sub-optimally-controlled Type 2 diabetes, following initiation of either exenatide, or insulin glargine, in addition to oral hypoglycaemic agents. Sensitivity analysis for a higher treatment discontinuation rate in exenatide patients was applied to the cohort in three different scenarios; (1) either ignored or (2) exenatide-failures excluded or (3) exenatide-failures switched to insulin glargine. Analyses were undertaken to evaluate the price sensitivity of exenatide in terms of relative cost effectiveness. Baseline cohort profiles and effectiveness data were taken from a published randomised controlled trial.
The relative cost-effectiveness of exenatide and insulin glargine was tested under a variety of conditions, in which insulin glargine was dominant in all cases. Using the most conservative of assumptions, the cost-effectiveness ratio of exenatide vs. insulin glargine at the current UK NHS price was -£29,149/QALY (insulin glargine dominant) and thus exenatide is not cost-effective when compared with insulin glargine, at the current UK NHS price.
This study evaluated the relative cost effectiveness of insulin glargine versus exenatide in the management of Type 2 diabetes using a published model. Given no significant difference in glycaemic control and applying the additional effectiveness of exenatide over insulin glargine, with respect to weight loss, and using the current UK NHS prices, insulin glargine was found to be dominant over exenatide in all modelled scenarios. With current clinical evidence, exenatide does not appear to represent a cost-effective treatment option for patients with Type 2 diabetes when compared to insulin glargine.
Levonorgestrel (LNg) is known for its marked progestational/contraceptive activity. As shown in animal experiments, however, high doses of LNg are required to elicit an androgenic response; in contrast, considerably lower doses of LNg are required for antiovulatory (contraceptive) action. Thus, a large dose separation exists between androgenic and contraceptive activity. When LNg is combined with an estrogen, as in the contraceptive formulations, the androgenic response is attenuated or negated. The results of recent clinical trials have demonstrated that the androgenic activity of LNg is not expressed at contraceptive doses, particularly when LNg is combined with ethinyl estradiol (EE), as in the low-dose monophasic/triphasic formulations (monophasic [Nordette]: 150 mcg LNg/30 mcg EE; triphasic [Triphasil/Trinordiol]: six days, 50 mcg LNg/30 mcg EE; five days, 75 mcg LNg/40 mcg EE; ten days, 125 mcg LNg/30 mcg EE). Clinical evidence from several trials confirms that sex hormone-binding globulin levels are increased, plasma androgen levels are decreased, and acne is markedly improved with the use of Triphasil and Nordette, suggesting a non-androgenic profile.