Philippe Lehert

Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial

Objectives To study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin. Design Multicentre randomised placebo controlled trial. Setting Outpatient clinics of three non-academic hospitals in the Netherlands. Participants 390 patients with type 2 diabetes receiving treatment with insulin. Intervention 850 mg metformin or placebo three times a day for 4.3 years. Main outcome measures Percentage change in vitamin B-12, folate, and homocysteine concentrations from baseline at4, 17, 30, 43, and 52 months. Results Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of −19% (95% confidence interval −24% to −14%; P<0.001) and in folate concentration of −5% (95% CI −10% to −0.4%; P=0.033), and an increase in homocysteine concentration of 5% (95% CI −1% to 11%; P=0.091). After adjustment for body mass index and smoking, no significant effect of metformin on folate concentrations was found. The absolute risk of vitamin B-12 deficiency (<150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group (95% CI 2.3 to 12.1; P=0.004), with a number needed to harm of 13.8 per 4.3 years (95% CI 43.5 to 8.3). The absolute risk of low vitamin B-12 concentration (150-220 pmol/l) at study end was 11.2 percentage points higher in the metformin group (95% CI 4.6 to 17.9; P=0.001), with a number needed to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 µmol/l (95% CI 18.8 to 30.0 µmol/l), compared with a mean homocysteine level of 18.1 µmol/l (95% CI 16.7 to 19.6 µmol/l; P=0.003) for patients with a low vitamin B-12 concentration and 14.9 µmol/l (95% CI 14.3 to 15.5 µmol/l; P<0.001 compared with vitamin B-12 deficiency; P=0.005 compared with low vitamin B-12) for patients with a normal vitamin B-12 concentration (>220 pmol/l). Conclusions Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered. Trial registration Clinicaltrials.gov NCT00375388.

The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals: Results of a meta-analysis

BACKGROUND A number of clinical trials have been undertaken to determine the efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals. However, the reported differences in patient populations, treatment duration, and study endpoints make comparisons difficult. An assessment of the efficacy of treatment with acamprosate was, therefore, undertaken using meta-analytical techniques. METHODS All randomized, placebo-controlled trials (RCTs) that fulfilled predetermined criteria were identified using (1) a language unrestricted search of 10 electronic databases; (2) a manual search of relevant journals, symposia, and conference proceedings; (3) cross-referencing of all identified publications; (4) personal communications with investigators; and (5) scrutiny of Merck-Santés internal reports of all European trials. Study quality was assessed, independently, by three blinded workers. Key outcome data were identified; some outcome variables were recalculated to ensure consistency across trials. The primary outcome measure was continuous abstinence at 6 months; abstinence rates were determined by estimating Relative Benefit (RB). RESULTS A total of 19 published 1 unpublished RCTs were identified that fulfilled the selection criteria; 3 were excluded because the documentation available was insufficient to allow adequate assessment. The remaining 17 studies, which included 4087 individuals, 53% of whom received active drug, were of good quality and were otherwise reasonably comparable. There was no evidence of publication bias. Continuous abstinence rates at 6 months were significantly higher in the acamprosate-treated patients (acamprosate, 36.1%; placebo, 23.4%; RB, 1.47; [95% confidence intervals (CI): 1.29-1.69]; p < 0.001). This effect was observed independently of the method used for assigning missing data. The effect sizes in abstinent rates at 3, 6, and 12 months were 1.33, 1.50, and 1.95, respectively. At 12 months, the overall pooled difference in success rates between acamprosate and placebo was 13.3% (95% CI, 7.8-18.7%; number needed to treat, 7.5). Acamprosate also had a modest but significant beneficial effect on retention (6.01%; [95% CI, 2.90-8.82]; p = 0.0106). CONCLUSION Acamprosate has a significant beneficial effect in enhancing abstinence in recently detoxified, alcohol-dependent individuals.

Long-term Effects of Metformin on Metabolism and Microvascular and Macrovascular Disease in Patients With Type 2 Diabetes Mellitus

BACKGROUND We investigated whether metformin hydrochloride has sustained beneficial metabolic and (cardio) vascular effects in patients with type 2 diabetes mellitus (DM2). METHODS We studied 390 patients treated with insulin in the outpatient clinics of 3 hospitals in a randomized, placebo-controlled trial with a follow-up period of 4.3 years. Either metformin hydrochloride, 850 mg, or placebo (1-3 times daily) was added to insulin therapy. The primary end point was an aggregate of microvascular and macrovascular morbidity and mortality. The secondary end points were microvascular and macrovascular morbidity and mortality, as separate aggregate scores. In addition, effects on hemoglobin A(1c) (HbA(1c)), insulin requirement, lipid levels, blood pressure, body weight, and body mass index were analyzed. RESULTS Metformin treatment prevented weight gain (mean weight gain, -3.07 kg [range, -3.85 to -2.28 kg]; P < .001), improved glycemic control (mean reduction in HbA(1c) level, 0.4% percentage point [95% CI, 0.55-0.25]; P < .001) (where CI indicates confidence interval), despite the aim of similar glycemic control in both groups, and reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI, 24.91-14.36 IU/d]; P < .001). Metformin was not associated with an improvement in the primary end point. It was, however, associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61 (95% CI, 0.40-0.94; P = .02), which was partly explained by the difference in weight. The number needed to treat to prevent 1 macrovascular end point was 16.1 (95% CI, 9.2-66.6). CONCLUSIONS Metformin, added to insulin in patients with DM2, improved body weight, glycemic control, and insulin requirements but did not improve the primary end point. Metformin did, however, reduce the risk of macrovascular disease after a follow-up period of 4.3 years. These sustained beneficial effects support the policy to continue metformin treatment after the introduction of insulin in any patient with DM2, unless contraindicated. Trial Registration ClinicalTrials.gov Identifier: NCT00375388.

An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin−/− mice and patients

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, direct onsets of rapid eye movement (REM) sleep from wakefulness (DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H(3)-receptor agonist. In narcoleptic orexin(-/-) mice, tiprolisant enhanced HA and noradrenaline neuronal activity, promoted wakefulness and decreased abnormal DREMs, all effects being amplified by co-administration of modafinil, a currently-prescribed wake-promoting drug. In a pilot single-blind trial on 22 patients receiving a placebo followed by tiprolisant, both for 1 week, the Epworth Sleepiness Scale (ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo (p>0.05) and 5.9 with tiprolisant (p<0.001). Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant dosing. H(3)-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.

The menopausal transition: a 9-year prospective population-based study. The Melbourne Women's Midlife Health Project

Objectives To describe the natural history of the menopause in Australian-born women. To determine the hormonal changes relating to the menopausal transition (MT) and how these affect quality of life, bone mineral density, body composition, cardiovascular disease (CVD) risk and memory. Design A 9-year prospective, observational study of a population-based sample of 438 Australian-born women aged 45–55 years at baseline. By the 9th year, the retention rate was 88%. Interviews, blood sampling, menstrual calendars, quality of life and physical measures were taken annually, and bone mineral density was measured bi-annually. Results The late MT coincides with changes in estradiol, follicle stimulating hormone, and free testosterone index, decreases in bone density and mastalgia, and increases in central adiposity, vasomotor symptoms, insomnia and vaginal dryness. Levels of total testosterone and dehydroepiandrosterone sulfate are unchanged by the MT. An increase in CVD risk was associated with increases in weight and free testosterone index and a decrease in estradiol. Depressed mood is increased by symptoms and by stressors occurring in the MT. Sexual functioning significantly deteriorates with the MT and aging, but relational factors have major effects. Menstrual cycles became more variable and longer closer to the final menstrual period. Conclusions As hormonal changes during the MT directly or indirectly adversely affect quality of life, body composition and CVD risk, maintenance of health parameters in the premenopausal years is crucial for a healthy postmenopause.

Effects of short‐term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo‐controlled trial

Abstract.  Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJM, Stehouwer CDA (Bethesda General Hospital, Hoogeveen, The Netherlands; University of Mons, Mons, Belgium; Merck Nederland B.V., Amsterdam; Deaconesses’ Hospital, Meppel; Aleida Kramer Hospital, Coevorden; and Vrije Universiteit Medical Centre, Amsterdam; The Netherlands). Effects of short‐term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo‐controlled trial. J Intern Med 2003; 254: 455–463.

Mood and the menopausal transition.

This study determined which variables affect womens mood state during the menopausal transition by using six prospective annual assessments of a community-based sample of 354 Australian mid-aged women. Repeated measures multivariate analysis of covariance found that negative mood scores decreased significantly over time and were not related to natural menopausal transition, follicle-stimulating hormone, estradiol, inhibin, age, or education. The magnitude of negative mood was significantly predicted by baseline reporting of premenstrual complaints, negative attitudes to ageing and menopause, and parity of one. During follow-up, the magnitude of negative mood was significantly adversely affected by: prior experience of negative mood, experience of bothersome symptoms, poor self-rated health, negative feelings for partner, no partner, current smoking, low exercise, daily hassles, and high stress. Negative mood was reduced by decreasing symptoms, improving health, positive feelings for partner, gaining a partner, and reducing stress. The menopausal transition had an indirect effect in amplifying the effect of reducing paid work, poor health, and daily hassles.

Pitolisant versus placebo or modafinil in patients with narcolepsy: A double-blind, randomised trial

BACKGROUND Narcolepsy is characterised by excessive daytime sleepiness (EDS) and cataplexy. Histamine neurons are crucial to maintain wakefulness. We assessed the safety and efficacy of pitolisant (previously called BF2.649), a selective histamine H3 receptor inverse agonist that activates these neurons, in patients with narcolepsy. METHODS For this double-blind, randomised, parallel-group controlled trial, we recruited patients with narcolepsy from 32 sleep disorder centres in five European countries. Patients were eligible if they were aged 18 years or older, had not taken psychostimulants for at least 14 days, and had EDS (defined as an Epworth Sleepiness Scale [ESS] score of at least 14). Using a computer-generated randomisation sequence, we randomly allocated patients to receive pitolisant, modafinil, or placebo (1:1:1). Treatment lasted 8 weeks: 3 weeks of flexible dosing according to investigators judgment (10 mg, 20 mg, or 40 mg a day of pitolisant; 100 mg, 200 mg or 400 mg a day of modafinil) followed by 5 weeks of stable dosing. Patients took four tablets a day in a double-dummy design to ensure masking. For the primary analysis, assessed in the intention-to-treat population, we assessed the superiority of pitolisant versus placebo, and the non-inferiority of pitolisant versus modafinil. This trial is registered with ClinicalTrials.gov, number NCT01067222. FINDINGS Between May 26, 2009, and June 30, 2010, we screened 110 patients, 95 of whom were eligible and randomly assigned to treatment: 30 to placebo, 32 to pitolisant, and 33 to modafinil. Over the 8-week treatment period, mean ESS score reductions were -3·4 (SD 4·2) in the placebo group, -5·8 (6·2) in the pitolisant group, and -6·9 (6·2) in the modafinil group. Our primary analysis of between-group differences in mean ESS score at endpoint (adjusted for baseline) showed pitolisant to be superior to placebo (difference -3·0, 95% CI -5·6 to -0·4; p=0·024), but not non-inferior to modafinil (difference 0·12, 95% CI -2·5 to 2·7; p=0·250). We recorded 22 adverse events with pitolisant, 26 with modafinil, and ten with placebo. Six severe adverse events were treatment-related: one with pitolisant (abdominal discomfort) and five with modafinil (abdominal pain, abnormal behaviour, amphetamine-like withdrawal symptoms, lymphoadenopathy, and inner ear disorders). INTERPRETATION Pitolisant at doses up to 40 mg was efficacious on EDS compared with placebo and well tolerated compared with modafinil. If these findings are substantiated in further studies, pitolisant could offer a new treatment option for patients with narcolepsy. FUNDING Bioprojet, France.

Factors affecting sexual functioning of women in the mid-life years.

OBJECTIVE To model the interaction of hormones, symptoms and psychosocial factors on womens sexuality during the menopausal transition. DESIGN AND METHODS A prospective, observational study was carried out of a community-based sample of 438 Australian-born women aged 45-55 years at baseline. The study comprised six annual assessments in the womens own homes utilizing a core questionnaire, with rating scales for well-being and daily hassles, and a Personal Experiences Questionnaire as a measure of sexual functioning. Levels of follicle stimulating hormone (FSH), estradiol and inhibin were measured annually. Statistical analysis was performed by structural equation modelling. RESULTS The retention rate was 90% (final sample size after exclusions, n = 354). The normal fit index for the global model obtained was 0.92. There is a significant direct effect of menopausal status on vaginal dryness/dyspareunia, and an indirect effect on sexual responsivity via a direct effect of menopausal status on symptoms, which then affect well-being. Menopausal status reflects hormonal status. Feelings for the partner and the partners sexual problems have direct effects on different aspects of sexual functioning. Other social variables such as paid work, interpersonal stress, daily hassles and educational level affect sexual functioning indirectly via effects on symptoms and well-being. CONCLUSIONS Psychosocial factors, symptoms and the menopausal transition affect womens sexual functioning during the mid-life years.

Sexual Function, Dysfunction, and Sexual Distress in a Prospective, Population‐Based Sample of Mid‐Aged, Australian‐Born Women

INTRODUCTION Previous, population-based studies investigating the risk factors for sexual distress have not drawn on longitudinal data. AIMS Determine the prevalence of sexual distress and dysfunction, explore factors associated with/predictive of sexual distress, and describe changes in sexual function over a decade in a population-based sample of mid-aged women. METHODS Eleven-year prospective study of Australian-born women, aged 45-55 years, and menstruating at baseline. Short Personal Experiences Questionnaire (SPEQ) was completed in years 1 to 8 and 11 of follow-up. Female Sexual Distress Scale (FSDS) was completed in the 11th year of follow-up. MAIN OUTCOME MEASURES Validated outcome measures were the SPEQ (total sex score <or=7 indicates low sexual function) and FSDS (score >or=15 indicates sexual distress). RESULTS Two hundred fifty-seven women were interviewed in the 11th year of follow-up. All domains of sexual function declined significantly in the decade studied. Women using hormone therapy in year 11 had significantly greater responsivity and higher frequency of sexual activities than nonusers. Two hundred four women completed both the FSDS and SPEQ questionnaires. One hundred sixty-six (81%) women had an SPEQ score <or=7 of whom 34 (17% of the total sample) had an FSDS score >or=15, and were classified as having female sexual dysfunction. The multiple logistic regression analysis found that female sexual distress was concurrently associated with higher depression scores (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.10, 1.56) and more negative feelings for partner (OR 0.49, 95% CI 0.32, 0.76) and predicted by prior negative feelings for partner (OR 0.31, 95% CI 0.14, 0.70), and a greater decline in total sex score (OR 0.77, 95% CI 0.59, 0.99). CONCLUSIONS By the end of the sixth decade, women have low levels of sexual function. Hormone therapy may help these women maintain sexual function. A minority of these mostly postmenopausal women are significantly distressed about low sexual function. Sexual distress is associated with depression and relationship factors.