Reflections of maternity service users and midwives' on the co-creation of interventions to support midwives addressing alcohol during antenatal care.

BACKGROUND: There are divergent perspectives between midwives and pregnant women on how alcohol consumption during pregnancy could be addressed. Co-creation is an approach where lay people and professionals work together as equal partners, offering the opportunity to bridge the gap. OBJECTIVES: Our aim was to evaluate how well we carried out authentic co-creation of an intervention to support midwives have a dialogue about alcohol consumption with pregnant women. PATIENT INVOLVEMENT: Recent maternity service users including women with experience of harm due to alcohol during pregnancy provided feedback on the design, conduct and dissemination of the study. METHODS: An iterative co-creation approach rooted in participatory research methods was used. Five online workshops were carried out with thirteen midwives and six maternity service users via Zoom July-August 2021. Data were analysed using the core values of co-create as a framework: equality, inclusivity, holistic, resource, positivity, transparency, iterative, and sustainability. RESULTS: The co-creation process was productive and rewarding to midwives and maternity service users. There were positive experiences across the co-creation framework with some unintended positive consequences for maternity-service users. DISCUSSION: This evaluation provides new knowledge on how well the co-creation process worked in relation to research involving a sensitive topic that can invite stigma. Co-creation projects require generous time and financial resources to ensure a high-quality process and robust outcome for all. PRACTICAL VALUE: Co-creation of strategies involving both service providers and service users have potential to facilitate evidence-based practice. FUNDING: This research is funded by the National Institute for Health Research (Reference: NIHR201128).

Beta-cell response to metformin-glibenclamide combination tablets (Glucovance) in patients with type 2 diabetes.

This exploratory double-blind, randomised, 20-week study evaluated the mechanism of action of metformin-glibenclamide combination tablets (Glucovance) vs. metformin and glibenclamide in 50 type 2 diabetes patients inadequately controlled by diet and exercise. A glycaemic target of HbA1C 7.0% was used. Final HbA(1C), fasting glucose and post-oral glucose tolerance test (OGTT) glucose were similar between groups, although average doses of metformin and glibenclamide from combination tablets (708 and 3.5 mg) were lower than monotherapy doses (1500 and 6.6 mg). Second-phase insulin during a hyperglycaemic clamp increased by 93% with combination tablets, 36% with metformin and 46% with glibenclamide. The insulin response post-OGTT was more rapid with the combination tablets vs. glibenclamide. First-phase insulin responses improved modestly in all groups, possibly due to reduced glucotoxicity. Changes in insulin sensitivity were minor. Larger beta-cell responses between combination tablets and glibenclamide may reflect more rapid glibenclamide absorption.

Durable efficacy of metformin/glibenclamide combination tablets (Glucovance) during 52 weeks of open-label treatment in type 2 diabetic patients with hyperglycaemia despite previous sulphonylurea monotherapy.

Oral anti-diabetic combinations that address insulin resistance and beta-cell dysfunction (e.g. metformin and glibenclamide) represent a rational therapeutic option for patients uncontrolled on monotherapy. A 52-week, open-label extension to a double-blind study evaluated metformin-glibenclamide combination tablets (Glucovance) in 477 patients with hyperglycaemia despite sulphonylurea therapy. Reductions in HbA1C were maintained, with a mean reduction of -1.7% after 52 weeks, compared with the baseline value for the double-blind trial. Eighty-five patients receiving 4 x 500 mg/2.5 mg tablets daily displayed a marked improvement in HbA1c following up-titration to a regimen of 2 x 500 mg/2.5 mg + 3 x 500 mg/5 mg tablets. Lipid profiles improved significantly. The combination tablets were well tolerated: 11.1% of patients reported hypoglycaemic symptoms (all either mild or moderate severity). No patient withdrew or required pharmacologic intervention for hypoglycaemia. Metformin-glibenclamide combination tablets are an effective and well-tolerated therapeutic option for intensifying oral anti-diabetic therapy.

The development of an oral antidiabetic combination tablet: design, evaluation and clinical benefits for patients with type 2 diabetes.

Type 2 diabetes is a chronic and progressive disease. Oral antidiabetic monotherapies directly address only one defect as their primary mechanism of action, and do not control blood glucose sufficiently well to meet current glycaemic targets. In consequence, most patients need combination therapy within a few years. However, the co-administration of two or more oral antidiabetic drugs may render treatment regimens difficult to follow. Combining oral antidiabetic agents into a single tablet provides a means of intensifying antidiabetic therapy while supporting good patient compliance. An insulin sensitiser and an insulin secretagogue represent a rational oral antidiabetic combination, as they address the dual endocrine defects of insulin resistance and impaired beta-cell function in type 2 diabetes. Nevertheless, the components of a combination tablet must be carefully chosen. Metformin (an insulin sensitiser) and glibenclamide (an insulin secretagogue) are well supported by decades of clinical evidence, and the pharmacokinetics of these agents support twice-daily co-administration. The final technical challenge is to optimise their delivery within a single-tablet combination. A recently-introduced metformin-glibenclamide combination tablet (Glucovance) has been extensively studied in well-designed clinical trials, where it has been shown to be more effective than its component monotherapies in controlling fasting and postprandial glycaemia. This treatment provides a case study in the development of a single-tablet oral antidiabetic combination, in terms of the pharmacokinetic issues facing the development of this preparation, and the implications of the pharmacokinetic properties of the components of the combination tablet on their pharmacodynamic actions and risk-benefit profile.

Influence of initial hyperglycaemia, weight and age on the blood glucose lowering efficacy and incidence of hypoglycaemic symptoms with a single-tablet metformin-glibenclamide therapy (Glucovance) in type 2 diabetes.

AIM: To evaluate the efficacy and incidence of hypoglycaemic symptoms associated with fixed combinations of metformin and glibenclamide (glyburide in the USA) formulated within a single tablet (tablet strengths 250 mg/1.25 mg, 500 mg/2.5 mg and 500 mg/5 mg), in comparison with metformin 500 mg and glibenclamide 2.5-5 mg monotherapy, in clinically important patient subgroups within the type 2 diabetic population. METHODS: A total of 1856 patients from three randomized, double-blind, multicentre, parallel-group clinical trials were stratified at baseline according to HbA1C (< 8% or > or = 8%), age (< 65 years or > or = 65 years) and body mass index (BMI; < 28 kg/m2 or > or = 28 kg/m2). The effects of study treatments on HbA1C and the incidence of hypoglycaemic symptoms were determined in each subgroup. RESULTS: The combination treatments were more effective than either monotherapy irrespective of baseline HbA1C, age or BMI in each trial. Antihyperglycaemic effects were greater in patients with HbA1C > or = 8% at baseline, especially with the combinations. The majority of hypoglycaemic symptoms with glibenclamide-containing treatments occurred in patients with HbA1C < 8% at baseline. Neither age nor BMI had a marked effect on the efficacy of the combination treatments, and there was no increase in hypoglycaemic symptoms in older patients. CONCLUSIONS: Single-tablet metformin-glibenclamide combination treatment is more effective than metformin or glibenclamide monotherapy, and is well tolerated in patients with hyperglycaemia inadequately controlled by diet and exercise or antidiabetic monotherapy, irrespective of their severity of hyperglycaemia at baseline, age or weight.

Differential effects of metformin on bile salt absorption from the jejunum and ileum.

AIMS: The antidiabetic drug metformin is often associated with a small reduction in total circulating cholesterol, but the mechanism responsible is unknown. As bile salts contribute significantly to cholesterol homeostasis, this study has investigated the effect of metformin on the absorption of bile salts by the jejunum and ileum, and their transfer into bile. METHODS: Sodium-[1-14C]-glycocholate was administered into the jejunum or ileum of anaesthetized rats with and without metformin (250 mg/kg). Appearance of 14C-glycocholate in plasma and bile was followed for 150 min. RESULTS: Absorption of 14C-glycocholate from the ileum, which is a high-capacity active process, was 10-fold greater than absorption from the jejunum, which is mainly a passive process. Metformin increased threefold the absorption of 14C-glycocholate from the jejunum. Metformin similarly increased the appearance of jejunal 14C-glycocholate in plasma and bile. In contrast to the jejunum, absorption of 14C-glycocholate from the ileum was suppressed by more than half with metformin. This was associated with corresponding reductions of 14C-glycocholate in plasma and bile. DISCUSSION: Thus, metformin induced a large suppression of active bile salt absorption from the ileum compared with a small increase in passive absorption from the jejunum. This suggests that the ileal effect of metformin to reduce overall bile salt absorption could contribute to the modest cholesterol-lowering effect of this drug.

Effects of metformin on bile salt transport by monolayers of human intestinal Caco-2 cells.

The antidiabetic biguanide metformin has been shown to increase faecal excretion of bile salts in type 2 diabetes. Cultured human intestinal Caco-2 cell monolayers provide a model of human enterocytes. These monolayers are used here to determine the effect of metformin on the secondary-active, sodium-linked transfer of 14C-glycocholate from the apical (brush border) to the basolateral (serosal) surface. During 24-h incubations, 10-2 mol/l metformin significantly reduced 14C-glycocholate transfer. This could not be attributed to alterations of monolayer integrity or Na+-K+ ATPase pump activity. For example, the secondary-active transport of glucose and proline was not interrupted, and the inhibitory effect of metformin on bile salt transport was additive to the inhibitory effect of ouabain. The results suggest that metformin can act directly on intestinal enterocytes to reduce the active transfer of bile salts by a mechanism that is independent of Na+-K+ ATPase activity.

Improved glycaemic control with metformin-glibenclamide combined tablet therapy (Glucovance) in Type 2 diabetic patients inadequately controlled on metformin.

AIMS: To evaluate the efficacy and safety of two dosage strengths of a single-tablet metformin-glibenclamide (glyburide) combination, compared with the respective monotherapies, in patients with Type 2 diabetes mellitus (DM) inadequately controlled by metformin monotherapy. METHODS: In this 16-week, double-blind, multicentre, parallel-group trial, 411 patients were randomized to receive metformin 500 mg, glibenclamide 5 mg, metformin-glibenclamide 500 mg/2.5 mg or metformin-glibenclamide 500 mg/5 mg, titrated with the intention to achieve fasting plasma glucose (FPG) < or = 7 mmol/l. RESULTS: Decreases in glycated haemoglobin (HbA1c) and FPG were greater (P < 0.05) for metformin-glibenclamide 500 mg/2.5 mg (-1.20% and -2.62 mmol/l) and 500 mg/5 mg (-0.91% and -2.34 mmol/l), compared with metformin (-0.19% and -0.57 mmol/l) or glibenclamide (-0.33% and -0.73 mmol/l). HbA1c < 7% was achieved by 75% and 64% of patients receiving metformin-glibenclamide 500 mg/2.5 mg and 500 mg/5 mg, respectively, compared with 42% for glibenclamide and 38% for metformin (P = 0.001). These benefits were achieved at lower mean doses of metformin or glibenclamide with metformin-glibenclamide 500 mg/2.5 mg and 500 mg/5 mg (1225 mg/6.1 mg and 1170 mg/11.7 mg) than with glibenclamide (13.4 mg) or metformin (1660 mg). Treatment-related serious adverse events occurred in two patients receiving glibenclamide. Plasma lipid profiles were unaffected and mean changes in body weight were < or = 1.0 kg. CONCLUSIONS: Intensive management of Type 2 DM with a new metformin-glibenclamide combination tablet improved glycaemic control and facilitated the attainment of glycaemic targets at lower doses of metformin or glibenclamide compared with the respective monotherapies, without compromising tolerability.

United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol.

A 6-month randomized controlled study of acamprosate versus placebo in preventing relapse following withdrawal from alcohol was undertaken in 20 centres throughout the UK. Patients diagnosed as alcohol-dependent and detoxified within the preceding 5 weeks were randomly assigned to treatment with either acamprosate (A) 666 mg three times/day or identical placebo (P). A total of 664 patients were screened; 581 were entered into the treatment phase. One-third were episodic drinkers, 84% were male, 44% were unmarried and 48% were unemployed. Medication was first taken on average 24 days after the start of detoxification; 32% of patients had already relapsed by this time. The 6-month study period was completed by 35% of patients; adverse events led to withdrawal of a further 14% (A) and 9% (P) respectively. Compliance was poor in that, by the end of the second week, only 57% of patients were judged to be taking at least 90% of their tablets. The mean total of abstinent days achieved was 77 (A) and 81 (P). Complete abstinence for 6 months was achieved by 12% (A) and 11% (P); drinking remained within controlled limits in a further 3% (A) and 6% (P). An effect of acamprosate on consumption was not seen when subgroups, including those defined by the Lesch typology, were analysed separately. However, the mean percentage reduction in craving for alcohol measured on a visual analogue scale was greater in the acamprosate, than placebo, patients at week 2 and week 4 (P<0.001) and the mean decrease in the Hamilton Anxiety score at the 4th week was greater in the acamprosate than placebo patients (P = 0.017). In comparison with other published trials of acamprosate, patients started study medication after a longer time following detoxification, had more often recommenced drinking before medication was started and had a higher drop-out rate, and this might have contributed to the lack of a treatment effect in this study.

A risk-benefit assessment of metformin in type 2 diabetes mellitus.

Metformin has been used for over 40 years as an effective glucose-lowering agent in type 2 (noninsulin-dependent) diabetes mellitus. Typically it reduces basal and postprandial hyperglycaemia by about 25% in more than 90% of patients when either given alone or coadministered with other therapies including insulin during a programme of managed care. Metformin counters insulin resistance and offers benefits against many features of the insulin resistance syndrome (Syndrome X) by preventing bodyweight gain, reducing hyperinsulinaemia and improving the lipid profile. In contrast to sulphonylureas, metformin does not increase insulin secretion or cause serious hypoglycaemia. Treatment of type 2 diabetes mellitus with metformin from diagnosis also offers greater protection against the chronic vascular complications of type 2 diabetes mellitus. The most serious complication associated with metformin is lactic acidosis which has an incidence of about 0.03 cases per 1000 patients years of treatment and a mortality risk of about 0.015 per 1000 patient-years. Most cases occur in patients who are wrongly prescribed the drug, particularly patients with impaired renal function (e.g. serum creatinine level > 130 micromol/L or > 1.5 g/L). Other major contraindications include congestive heart failure, hypoxic states and advanced liver disease. Serious adverse events with metformin are predictable rather than spontaneous and are potentially preventable if the prescribing guidelines are respected. Gastrointestinal adverse effects, notably diarrhoea, occur in less than 20% of patients and remit when the dosage is reduced. The life-threatening risks associated with metformin are rare and could mostly be avoided by strict adherence to the prescribing guidelines. Given the 4 decades of clinical experience with metformin, its antihyperglycaemic efficacy and benefits against Syndrome X, metformin offers a very favourable risk-benefit assessment when compared with the chronic morbidity and premature mortality among patients with type 2 diabetes mellitus.

Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus.

Gastrointestinal symptoms can be a limiting factor in optimizing metformin therapy, particularly at the onset of treatment. The underlying cause remains unclear. We have investigated whether metformin changes oral-caecal transit and if it causes bile salt malabsorption using the lactulose breath test and orally administered 14C-glycocholate followed by breath 14CO2 measurement over 6 h and stool collection for 72 h, respectively. Twenty-four diet and/or sulphonylurea treated patients underwent 7 days of baseline investigations before entering a randomized double-blind crossover study of 21 days duration with either metformin (850 mg bd) or placebo. No difference was observed in the oral-caecal transit time but a change in fasting plasma glucose was observed of 2.6 mmol l-1 (95% CI 1.3, 3.8). Significant increases in percentage 14CO2 breath elimination were observed during treatment with metformin (9.7 +/- 6.3) compared with placebo (3.1 +/- 1.9) p = 0.020. In addition, percentage faecal 14C bile salt excretion was increased with metformin (17.2 +/- 9.9 vs 10.1 +/- 6.9) p = 0.037. A significant association (p = 0.002) emerged for stool bile salt content and liquidity of the stool. We conclude that metformin may cause gastrointestinal disturbances by reducing ileal bile salt reabsorption leading to elevated colonic bile salt concentrations.

The SECCAT Survey: II. The Alcohol Related Problems Questionnaire as a proxy for resource costs and quality of life in alcoholism treatment. Study of Socio-Economic Consequences and Costs of Alcoholism and Treatment.

An interview was obtained with 212 patients who had, at a point 12 months previously, been in contact with an alcohol problems clinic. Quality of life (SF-36) was measured and for the preceding 6 months the cost of health and social service resource use was estimated, together with the total abstinent (or controlled drinking) days accrued. Alcohol related health, personal and social problems experienced during that period were elicited using a brief 11-item questionnaire, the Alcohol Related Problems Questionnaire (ARPQ). The estimate of costs correlated more strongly with the ARPQ score (r = -0.32, P = 0.0001) than with abstinent days (r = 0.03, n.s.) or controlled drinking months (r = -0.21, P = 0.002). The lack of relation of total abstinent days to cost is partly because abstainers tended to use considerable alcohol problems clinic resources. ARPQ scores indicating more problems were associated with lower quality of life. The ARPQ can serve as a proxy for resource use and quality of life in alcoholism treatment.

The SECCAT survey: I. The costs and consequences of alcoholism.

The SECCAT survey assessed the Socio-Economic Costs and Consequences of Alcoholism Treatment. Basic demographic and health service resource use data (for a previous 6-month period) were obtained fro a cohort of 586 eligible patients who had had treatment at the Alcohol Problems Clinic (APC) in Edinburgh. The cohort was 75% male with a mean age of 46.0 years. Seventy-six per cent had an initial diagnosis of alcohol dependence and 21% alcohol abuse. Use of health services was highly variable. Thirty-six per cent agreed to be interviewed to provide data on their level of abstinence, on resource use, on quality of life (SF-36), on socio-economic characteristics and key adverse events. These 212 individuals had similar age and sex ratios to the full cohort, but alcohol abusers were under-represented. Nineteen patients reported no days of abstinence and 41 were abstinent over the whole 6-month period. Patients experienced a much poorer quality of life than a normal population in terms of all dimensions of the SF-36. The average total health care costs of the interviewed patients were 1134 pounds of which 38% were related to treatment at the APC. Analysis suggests that alcohol-dependent patients make substantially more costly use of resources than abusers and experience a much poorer quality of life. No clear relationship of cost to degree of abstinence has been found. There is a clear and consistent relationship of SF-36 scores and drinking behavior.