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Metformin Treatment (metformin + treatment)

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The different mechanisms of insulin sensitizers to prevent type 2 diabetes in OLETF rats

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2007
Sung Hee Choi
Abstract Objective To investigate the effects of pioglitazone and metformin treatment during pre-diabetic period for the prevention of diabetes in a rat model. Methods OLETF rats aged 18-weeks, were treated with pioglitazone (10 mg/kg/day) and metformin (300 mg/kg/day) for 10 weeks from their pre-diabetic period. We measured weight, lipid profiles, fat distribution, glucose tolerance, and pancreatic insulin content. Results Prominent weight gain (mostly subcutaneous fat area) was observed in the pioglitazone-treated OLETF (O-P) rats versus significant weight loss was observed in the metformin-treated OLETF (O-M) rats. Pioglitazone reversed the serum triglyceride (TG) and FFAs levels to normal (TG 0.46 ± 0.04 vs 0.88 ± 0.05 mmol/l in LETO). At the age of 28 weeks, the O-P rats showed completely normal glucose tolerance, and the glucose disposal rate (GDR) was markedly improved (25.6 ± 0.4 vs 20.6 ± 0.5 mg/min/kg in O-C, p < 0.05). The O-M rats also showed an improved fasting glucose and GDR level, but not as much as those with O-P rats. The pancreas insulin contents were much improved in the O-P rats (22.9 ± 1.2 vs 18.8 ± 1.3 nmol/pancreas in O-M rats, p < 0.05) with histological improvement. Conclusion The pre-diabetic treatment with pioglitazone, despite significant weight gain, completely prevents to develop diabetes and enhances beta cell function with preservation of islet cell changes. Metformin treatment was also effective, but mainly by ameliorating the insulin resistance with marked reduction in body weight. The reversal of dyslipidaemia and the fat redistribution might contribute to the greater improvement of pioglitazone treatment compared to metformin in OLETF rats. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Metabolic effects of metformin in patients with impaired glucose tolerance

DIABETIC MEDICINE, Issue 7 2001
M. Lehtovirta
Abstract Aims To assess the effect of metformin on insulin sensitivity, glucose tolerance and components of the metabolic syndrome in patients with impaired glucose tolerance (IGT). Methods Forty first-degree relatives of patients with Type 2 diabetes fulfilling WHO criteria for IGT and participating in the Botnia study in Finland were randomized to treatment with either metformin 500 mg b.i.d. or placebo for 6 months. An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp in combination with indirect calorimetry was performed at 0 and 6 months. The patients were followed after stopping treatment for another 6 months in an open trial and a repeat OGTT was performed at 12 months. Results Metformin treatment resulted in a 20% improvement in insulin-stimulated glucose metabolism (from 28.7 ± 13 to 34.4 ± 10.7 µmol/kg fat-free mass (FFM)/min) compared with placebo (P = 0.01), which was primarily due to an increase in glucose oxidation (from 16.6 ± 3.6 to 19.1 ± 4.4 µmol/kg FFM; P = 0.03) These changes were associated with a minimal improvement in glucose tolerance, which was maintained after 12 months. Conclusions Metformin improves insulin sensitivity in subjects with IGT primarily by reversal of the glucose fatty acid cycle. Obviously large multicentre studies are needed to establish whether these effects are sufficient to prevent progression to manifest Type 2 diabetes and associated cardiovascular morbidity and mortality. Diabet. Med. 18, 578,583 (2001) [source]

Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris

EXPERIMENTAL DERMATOLOGY, Issue 10 2009
Bodo C. Melnik
Abstract:, It is the purpose of this viewpoint article to delineate the regulatory network of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signalling during puberty, associated hormonal changes in adrenal and gonadal androgen metabolism, and the impact of dietary factors and smoking involved in the pathogenesis of acne. The key regulator IGF-1 rises during puberty by the action of increased GH secretion and correlates well with the clinical course of acne. In acne patients, associations between serum levels of IGF-1, dehydroepiandrosterone sulphate, dihydrotestosterone, acne lesion counts and facial sebum secretion rate have been reported. IGF-1 stimulates 5,-reductase, adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation and lipogenesis. Milk consumption results in a significant increase in insulin and IGF-1 serum levels comparable with high glycaemic food. Insulin induces hepatic IGF-1 secretion, and both hormones amplify the stimulatory effect of GH on sebocytes and augment mitogenic downstream signalling pathways of insulin receptors, IGF-1 receptor and fibroblast growth factor receptor-2b. Acne is proposed to be an IGF-1-mediated disease, modified by diets and smoking increasing insulin/IGF1-signalling. Metformin treatment, and diets low in milk protein content and glycaemic index reduce increased IGF-1 signalling. Persistent acne in adulthood with high IGF-1 levels may be considered as an indicator for increased risk of cancer, which may require appropriate dietary intervention as well as treatment with insulin-sensitizing agents. [source]

Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome

CLINICAL ENDOCRINOLOGY, Issue 6 2004
Joachim Spranger
Summary objective, The polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance predisposing to diabetes mellitus type 2 and atherosclerosis. Adiponectin is a recently discovered adipocytokine with insulin-sensitizing and putative antiatherosclerotic properties. The aim of the study was to elucidate determinants of circulating adiponectin levels and to investigate the potential role of adiponectin in insulin resistance in PCOS women. patients and measurements, Plasma adiponectin and parameters of obesity, insulin resistance and hyperandrogenism were measured In 62 women with PCOS and in 35 healthy female controls. results, Both in PCOS and controls, adiponectin levels were lower in overweight or obese women than in normal-weight women, without any difference between PCOS and controls after adjustment for body mass index (BMI). In PCOS and in controls there was a significant correlation of adiponectin with BMI (r = ,0·516, P < 0·001), fasting insulin (r = ,0·404, P < 0·001), homeostasis model sensitivity (HOMA %S) (r = ,0·424, P < 0·001) and testosterone (r = ,0·279, P < 0·01), but no correlation with androstenedione (r = ,0·112, P = 0·325), 17-OH-progesterone (r =,0·031, P = 0·784) or the LH/FSH ratio (r =,0·033, P = 0·753). Multiple linear regression analysis revealed that BMI and HOMA %S but not testosterone were independently associated with adiponectin plasma levels, explaining 16% (BMI) and 13% (HOMA %S) of the variability of adiponectin, respectively. In PCOS patients insulin sensitivity, as indicated by continuous infusion of glucose with model assessment (CIGMA %S) was significantly correlated with adiponectin (r = 0·55; P < 0·001), BMI (r =,0·575; P < 0·001), waist-to-hip ratio (WHR) (r =,0·48; P = 0·001), body fat mass assessed by dual-energy X-ray-absorptiometry (DEXA) [Dexa-fat (total) (r = ,0·61; P < 0·001) and Dexa-fat (trunk) (r = ,0·59; P < 0·001)] and with testosterone (r = ,0·42; P = 0·001). Multiple linear regression analysis demonstrated that markers of obesity such as BMI, total or truncal fat mass, age and adiponectin were independently associated with CIGMA %S, and that circulating adiponectin accounted for about 18% of the degree of insulin resistance in PCOS. By contrast, testosterone was not a significant factor, suggesting that PCOS per se did not affect insulin sensitivity independent from obesity, age and adiponectin. Metformin treatment for 6 months in insulin-resistant PCOS women (n = 9) had no effect on plasma adiponectin (P = 0·59) despite significant loss of weight and fat mass and improvement in hyperandrogenaemia. conclusions, PCOS per se is not associated with decreased levels of plasma adiponectin. However, circulating adiponectin is independently associated with the degree of insulin resistance in PCOS women and may contribute to the development and/or maintenance of insulin resistance independent from adiposity. [source]

Oral antidiabetic treatment in patients with coronary disease: Time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up

CLINICAL CARDIOLOGY, Issue 2 2001
Enriqe Z. Fisman M.D.
Abstract Background: A sulfonylurea ,usually glyburide,plus metformin constitute the most widely used oral antihyperglycemic combination in clinical practice. Both medications present undesirable cardiovascular effects. The issue whether the adverse effects of each of these pharmacologic agents may be additive and detrimental to the prognosis for coronary patients has not yet been specifically addressed. Hypothesis: This study was designed to examine the survival in type 2 diabetics with proven coronary artery disease (CAD) receiving a combined glyburide/metformin antihyperglycemic treatment over a long-term follow-up period. Methods: The study sample comprised 2,275 diabetic patients, aged 45,74 years, with proven CAD, who were screened but not included in the bezafibrate infarction prevention study. In addition. 9,047 nondiabetic patients with CAD represented a reference group. Diabetics were divided into four groups on the basis of their therapeutic regimen: diet alone (n = 990), glyburide (n = 953), metformin (n = 79), and a combination of the latter two (n = 253). Results: The diabetic groups presented similar clinical characteristics upon recruitment. Crude mortality rate after a 7.7-year follow-up was lower in nondiabetics (14 vs. 31.6%, p<0.001). Among diabetics, 720 patients died: 260 on diet (mortality 26.3%). 324 on glyburide (34%), 25 on metformin alone (31.6%), and 111 patients (43.9%) on combined treatment (p<0.000001). Time-related mortality was almost equal for patients on metformin and on combined therapy over an intermediate follow-up period of 4 years (survival rates 0.80 and 0.79, respectively). The group on combined treatment presented the worst prognosis over the long-term follow-up, with a time-related survival rate of 0.59 after 7 years, versus 0.68 and 0.70 for glyburide and metformin, respectively. After adjustment to variables for prognosis, the use of the combined treatment was associated with an increased hazard ratio (HR) for all-cause mortality of 1.53 (95% confidence interval [CI] 1.20,1.96), whereas glyburide and metformin alone yielded HR 1.22 (95% CI 1.02,1.45) and HR 1.26 (95% CI 0.81,1.96), respectively. Conclusions: We conclude that after a 7.7-year follow-up, monotherapy with either glyburide or metformin in diabetic patients with CAD yielded a similar outcome and was associated with a modest increase in mortality. However, time-related mortality was markedly increased when a combined glyburide/metformin treatment was used. [source]

Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes

DIABETES OBESITY & METABOLISM, Issue 2 2010
T. Vilsbøll
Objective: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes. Methods: After a 2 week placebo run-in period, eligible patients inadequately controlled on long-acting, intermediate-acting or premixed insulin (HbA1c , 7.5% and , 11%), were randomised 1:1 to the addition of once-daily sitagliptin 100 mg or matching placebo over a 24-week study period. The study capped the proportion of randomised patients on insulin plus metformin at 75%. Further, the study capped the proportion of randomised patients on premixed insulin at 25%. The metformin dose and the insulin dose were to remain stable throughout the study. The primary endpoint was HbA1c change from baseline at week 24. Results: Mean baseline characteristics were similar between the sitagliptin (n = 322) and placebo (n = 319) groups, including HbA1c (8.7 vs. 8.6%), diabetes duration (13 vs. 12 years), body mass index (31.4 vs. 31.4 kg/m2), and total daily insulin dose (51 vs. 52 IU), respectively. At 24 weeks, the addition of sitagliptin significantly (p < 0.001) reduced HbA1c by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an HbA1c level < 7% while randomised to sitagliptin as compared with placebo (13 vs. 5% respectively; p < 0.001). Similar HbA1c reductions were observed in the patient strata defined by insulin type (long-acting and intermediate-acting insulins or premixed insulins) and by baseline metformin treatment. The addition of sitagliptin significantly (p < 0.001) reduced fasting plasma glucose by 15.0 mg/dl (0.8 mmol/l) and 2-h postmeal glucose by 36.1 mg/dl (2.0 mmol/l) relative to placebo. A higher incidence of adverse experiences was reported with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycaemia (sitagliptin, 16% vs. placebo, 8%). The number of hypoglycaemic events meeting the protocol-specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1). No significant change from baseline in body weight was observed in either group. Conclusion: In this 24-week study, the addition of sitagliptin to ongoing, stable-dose insulin therapy with or without concomitant metformin improved glycaemic control and was generally well tolerated in patients with type 2 diabetes. [source]

Reflecting on Type 2 Diabetes Prevention: More Questions than Answers!

DIABETES OBESITY & METABOLISM, Issue 2007
J. Rosenstock
Given the enormous public health and economic burden posed by the global epidemic of type 2 diabetes mellitus (T2DM), intervention in the prediabetes stage of disease to prevent progression to T2DM and its vascular complications seems the most sensible approach. Precisely how best to intervene remains the subject of much debate. Prudent lifestyle changes have been shown to significantly reduce the risk of progression in individuals with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Although lifestyle modifications are notoriously difficult to maintain, there is evidence that intensive intervention results in continued preventive benefit after the stopping of structured counselling. A number of drug therapies, including metformin, acarbose, orlistat and rosiglitazone, have also been proven effective in preventing progression from IFG/IGT, but unresolved issues still remain. Specifically, whether large numbers of individuals with glucose dysregulation who may never progress to T2DM should be exposed to the risk of pharmacological adverse effects is a topic of discussion and debate. Furthermore, there are limited data on the effectiveness of implementing interventions during the prediabetic state to prevent cardiovascular complications that may be hyperglycaemia related. A recent American Diabetes Association (ADA) consensus statement on IFG/IGT recommends lifestyle modification for individuals with IFG or IGT. Of note, the ADA consensus statement introduces the option of adding metformin treatment to lifestyle changes in those individuals who have combined IFG/IGT plus an additional risk factor for progression and who also have some features that increase the likelihood of benefiting from metformin treatment. The dipeptidyl peptidase-4 inhibitors are a new class of oral antidiabetic agents that, in addition to being effective in improving glycaemic control, may exert beneficial effects in preserving ,-cell function. These characteristics, combined with a low risk of hypoglycaemia, weight neutrality and what appears , so far , to be a relatively benign tolerability profile, make these agents intriguing candidates for preventive treatment. [source]

The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient well-being

DIABETES OBESITY & METABOLISM, Issue 1 2007
R. J. Moon
Aim:, As many overweight people with T1DM are insulin resistant, adjuvant therapy with insulin sensitising agents, such as metformin, may be beneficial. This study evaluated the effect of adjuvant metformin in T1DM on insulin sensitivity, diabetic control, body composition, quality of life (QOL) and treatment satisfaction. Materials and Methods:, A 3-month prospective open-labelled pilot study of 16 patients aged 18-40 with T1DM and body mass index (BMI) >25 kg/m2 was performed. The patients received 500-850 mg metformin twice daily. Insulin sensitivity, assessed by a frequently sampled intravenous glucose tolerance test [n=5], body composition, HbA1c and quality of life (QOL) were measured before and after treatment. A retrospective review of 30 patients with T1DM treated with metformin for at least 4 months was also performed. BMI, HbA1c and insulin requirements during metformin treatment was compared to pre-metformin data, and to patients treated with insulin only. Results:, In the pilot study, insulin sensitivity increased significantly from 0.86 ± 0.33 × 10,4/min/(µU/ml) to 1.17 ± 0.48 × 10,4/min/(µU/ml) after 3 months adjuvant therapy (p = 0.043). This was associated with a decreased insulin requirement and mean daily blood glucose. There were no significant changes in HbA1c or body composition. QOL significantly improved (p < 0.002). The retrospective review revealed an initial reduction in HbA1c (0.8 ± 1.4%, p = 0.001). This effect diminished with prolonged treatment. BMI decreased in patients remaining on metformin for a 2-year period (0.5 ± 0.5kg/m2, p = 0.042). Conclusion:, Adjuvant metformin can improve QOL, insulin sensitivity and glycaemic control in overweight adults with T1DM. [source]

Moxonidine improves glycaemic control in mildly hypertensive, overweight patients: a comparison with metformin

DIABETES OBESITY & METABOLISM, Issue 4 2006
Irina Chazova
Aim:, To compare the effects of moxonidine and metformin on glycaemic control in patients with impaired glucose tolerance and signs of the metabolic syndrome. Methods:, A multicentre, prospective, randomized, open-label study design was adopted with blinded endpoint evaluation. Patients ,40 years old, with impaired glucose tolerance (or diabetes mellitus treated with diet alone) and a body mass index (BMI) of at least 27 kg/m2 were treated twice daily with moxonidine 0.2 mg or metformin 500 mg for 16 weeks. Oral glucose tolerance test (OGTT) was performed at baseline and end-of-study; plasma insulin and plasma glucose levels were measured at 0, 60, 120 and 180 min after administration. Results:, With regard to effects on insulin [mean area under the curve (AUC) for insulin], the primary efficacy endpoint of the study, both drugs did not show equivalence. On the contrary, in the per protocol (PP) population, moxonidine statistically significantly (p = 0.025) decreased the AUC for insulin from baseline in the PP population; for metformin, the treatment effect on insulin was a small, net increase resulting in a statistically significant between-group difference of 16.2% (95% CI = 0.1,35.0). The change in mean insulin AUC was most marked in the subgroup of patients with higher sympathetic activity (heart rate >80 bpm). Mean fasting plasma glucose (FPG) levels and HbA1c levels were largely unchanged by moxonidine treatment but significantly decreased by metformin treatment. The difference between the groups was 14.7% (p = 0.0523) in the intent-to-treat (ITT) sample. By study end, both treatments had significantly increased the Matsuda Insulin Sensitivity Index (ISI) from baseline to a comparable extent: moxonidine by reducing plasma insulin after a glucose challenge, metformin by reducing FPG. BMI fell significantly in both groups and blood pressure normalized; both drugs were well tolerated. Conclusions:, Moxonidine improved insulin sensitivity in response to glucose challenge in patients with evidence of metabolic syndrome. This improvement resulted from a reduction in plasma insulin levels and was most marked in patients with high sympathetic drive at baseline. By enhancing insulin sensitivity, moxonidine treatment may help prevent the development of diabetes and thereby ameliorate the risk for cardiovascular disease. [source]

Effects of short-term metformin treatment on insulin sensitivity of blood glucose and free fatty acids

DIABETES OBESITY & METABOLISM, Issue 1 2004
S. Iannello
Aim:, Based on the known effect of metformin (MET) in improving insulin sensitivity in type 2 diabetes, with the scope to focus the effects on glycaemic and free fatty acids (FFA) levels, we studied the effects of a short-term treatment with this drug in obese subjects and obese patients with diabetes or family history of diabetes (FHD). We used a method to allow us to evaluate the possible difference of insulin sensibility with regard to the insulin action on glycaemia and blood FFA, both in the basal state and during oral glucose tolerance test (OGTT). Methods:, Insulin sensitivity was investigated before and after MET treatment (850 mg bid for 10 days) in seven obese subjects with normal glucose tolerance and without FHD and 13 obese patients with diabetes (n = 7) or FHD (n = 6). By using specifically designed formulae, we calculated four insulin-sensitivity indices (ISI) from basal level (b) and area values (a) (during OGTT) of insulinaemia, glycaemia (gly) or FFA (ffa), namely: ISI (gly)-b, ISI (gly)-a, ISI (ffa)-b and ISI (ffa)-a. Results:, In patients with diabetes or FHD, MET improved ISI (gly)-b (0.79 ± 0.06 vs. 0.59 ± 0.07, p < 0.001) and ISI (gly)-a (0.69 ± 0.09 vs. 0.51 ± 0.07, p < 0.05), whereas only minor changes occurred for ISI (ffa)-b and ISI (ffa)-a. In contrast, in simple obese subjects, MET induced further deterioration of both ISI (gly)-a (0.47 ± 0.07 vs. 0.64 ± 0.10, p < 0.01) and ISI (ffa)-a (0.43 ± 0.07 vs. 0.55 ± 0.08, p < 0.05). Fasting level and total area of lactate were high in the obese patients and were not affected by MET. A statistically significant increase (p < 0.01), however, was observed for the ,decremental' area of lactate in obese subjects with diabetes or FHD, which might probably contribute to the reduction of insulin resistance induced by the drug in these patients. Conclusions:, Although the low number of subjects studied precludes absolute conclusions, data would suggest that MET improved ISI towards glucose but not towards FFA, in the diabetic and ,prediabetic' obese patients, whereas worsened it in the obese subjects without FHD. Therefore, the effects of MET would not be secondary to changes of FFA but rather to a primary action of MET on glucose metabolism. Thus, utilization of MET to treat the insulin resistance in obesity is indicated only in the presence of alterations of glucose metabolism or FHD. [source]

The different mechanisms of insulin sensitizers to prevent type 2 diabetes in OLETF rats

Establishing pragmatic estimated GFR thresholds to guide metformin prescribing

DIABETIC MEDICINE, Issue 10 2007
J. S. Shaw
Abstract Aims, Renal impairment is a contraindication to metformin treatment because of the perceived increased risk of lactic acidosis. Current guidelines define renal impairment according to the serum creatinine of the individual, but this measure is being supplanted by the use of estimated glomerular filtration rate (eGFR) as it gives a closer estimate to true GFR. This study aimed to establish pragmatic eGFR limits for use in patients being considered for metformin treatment. Methods, Estimated GFR measurements corresponding to currently used metformin creatinine limits of 130 and 150 µmol/l were derived and then applied to 12 482 patients with diabetes in Hull and East Yorkshire. Results, Few patients with a serum creatinine of 130 or 150 µmol/l have an eGFR of < 30 ml/min/1.73 m2[chronic kidney disease (CKD) stage 4 or greater], while most are between 30 and 59 ml/min/1.73 m2 (CKD stage 3). When applied to the 12 482 patients (median age 67 years, interquartile range 56,75), males predominated when using creatinine cut-offs (13.6% of males and 8.3% of females had creatinine > 130 µmol/l; 8.2% males and 5.2% females > 150 µmol/l), but not using eGFR CKD thresholds (3.3% males and 4.7% females < 30 ml/min/1.73 m2; 20.8% males and 28.1% females eGFR 30,59 ml/min/1.73 m2). Similar proportions of patients as currently would have metformin withheld if using eGFR cut-offs between 30 and 49 ml/min/1.73 m2. Conclusions, We have proposed pragmatic eGFR limits to guide metformin prescribing in patients with renal impairment. CKD stage 4 or greater should be an absolute contraindication to metformin, while CKD stage 3 should alert clinicians to consider other risk factors before initiating or continuing treatment. [source]

The effect of metformin on measurements of insulin sensitivity and , cell response in 18 horses and ponies with insulin resistance

EQUINE VETERINARY JOURNAL, Issue 5 2008
A. E. Durham
Summary Reasons for performing study: Laminitis in equids is a very common debilitating disease, and insulin resistance (IR) and hyperinsulinaemia are increasingly recognised as important predisposing factors. Pharmacological modification of IR and hyperinsulinaemia might reduce the risk of laminitis. Hypothesis: Metformin, a drug commonly prescribed for treatment of human IR, may also decrease IR in equids. Methods: Eighteen horses and ponies with IR and recurrent laminitis were treated with 15 mg/kg bwt metformin per os q. 12 h. Each animal served as its own control by comparing pre- and post treatment proxies for IR, insulin sensitivity (IS) and pancreatic , cell function while controlling for possible dietary and managemental influences on IR. Results: Evidence of significantly improved IS and decreased pancreatic , cell secretion was found following metformin treatment. The magnitude of effect was greater at earlier resampling (6,14 days) than at later times (23,220 days). Apparent subjective clinical benefits were good but less favourable than effects on IR. Conclusions: Metformin is safe and appears to increase IS in equids. Potential relevance: Metformin may be indicated as a treatment for IR in equids. Further studies are required to define appropriate selection of subjects warranting therapy, dosing schedule and pharmacokinetics. [source]

Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome?

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 5 2008
Fauzia Haq Nawaz
Abstract Aim:, Polycystic ovarian syndrome (PCOS) is one of the most common endocrinopathies in women of reproductive age. It is associated with hyperinsulinemia and insulin resistance which is further aggravated during pregnancy. This mechanism has a pivotal role in the development of various complications during pregnancy. In the past few years, metformin, an insulin sensitizer, has been extensively evaluated for induction of ovulation. Its therapeutic use during pregnancy is, however, a recent strategy and is a debatable issue. At present, evidence is inadequate to support the long-term use of insulin-sensitizing agents during pregnancy. It is a challenge for both clinicians and researchers to provide good evidence of the safety of metformin for long-term use and during pregnancy. This study aimed to evaluate pregnancy outcomes in women with PCOS who conceived while on metformin treatment, and continued the medication for a variable length of time during pregnancy. Methods:, This case-control study was conducted from January 2005 to December 2006 at the antenatal clinics of the Department of Obstetrics and Gynecology, Aga Khan University, Karachi, Pakistan. The sample included 137 infertile women with PCOS; of these, 105 conceived while taking metformin (cases), while 32 conceived spontaneously without metformin (controls). Outcomes were measured in three groups of cases which were formed according to the duration of use of metformin during pregnancy. Comparison was made between these groups and women with PCOS who conceived spontaneously. Results:, All 137 women in this study had a confirmed diagnosis of PCOS (Rotterdam criteria). These women were followed up during their course of pregnancy; data forms were completed once they had delivered. Cases were divided into three groups: group A, 40 women who stopped metformin between 4,16 weeks of pregnancy; group B, 20 women who received metformin up until 32 weeks of gestation; and group C; 45 women who continued metformin throughout pregnancy. All the groups were matched by age, height and weight. Comparison was in terms of early and late pregnancy complications, intrauterine growth restriction and live birth rates. In groups A, B and C the rate of pregnancy-induced hypertension/pre-eclampsia was 43.7%, 33% and 13.9% respectively (P < 0.020). Rates of gestational diabetes requiring insulin treatment in groups A and B were 18.7% and 33.3% compared to 2.5% in group C (P < 0.004). The rate of intrauterine growth restriction was significantly low in group C: 2.5% compared to 19.2% and 16.6% in groups A and B respectively (P < 0.046). Frequency of preterm labor and live birth rate was significantly better in group C compared to groups A and B. Overall rate of miscarriages was 7.8%. Controls were comparable to group A in terms of early and late pregnancy complications. Conclusion:, In women with PCOS, continuous use of metformin during pregnancy significantly reduced the rate of miscarriage, gestational diabetes requiring insulin treatment and fetal growth restriction. No congenital anomaly, intrauterine death or stillbirth was reported in this study. [source]

Latest news and product developments

PRESCRIBER, Issue 11 2008
Article first published online: 18 JUN 200
New asthma guideline The BTS/SIGN guideline for the management of asthma has been updated. The diagnosis section has been rewritten, there is a new section on difficult asthma and the treatment sections have been updated. A new option at Step 3 (initial add-on therapy) is now the use of a combined budesonide/formoterol inhaler (Symbicort) as a reliever in addition to regular use as a preventer. This reflects evidence from the SMART trials, which showed that an average of one extra puff per day significantly reduced exacerbations and admissions (Br Med J 2007;335:513). Metformin matches insulin in pregnancy Metformin does not worsen perinatal outcomes compared with insulin in gestational diabetes and mothers prefer it, a study from Australia and New Zealand shows (N Engl J Med 2008;358:2003,15). Of the women randomised to metformin treatment, 93 per cent were still taking it at term and 46 had supplemental insulin. The combined incidence of neonatal hypoglycaemia, respiratory distress, need for phototherapy, birth trauma, five-minute Apgar score less than 7 or prematurity was 32 per cent with both treatments. There were no serious adverse events. More women said they would choose the same treatment again for metformin than insulin (77 vs 27 per cent). Same CV protection with antihypertensives There is no difference in protection against major cardiovascular events between different types of antihypertensives in young or older (65 or over) adults, according to the Blood Pressure Lowering Treatment Trialists' Collaboration. Its meta-analysis of 31 trials involving over 190 000 patients (BMJ Online 2008; doi:10.1136/bmj.39548.738 368.BE) found no significant difference by age on blood pressure reduction or risk reduction. Treatment may be chosen according to tolerability and cost as long as effective blood pressure reduction is achieved, the authors conclude. Older people are at greater absolute risk and treatment therefore offers larger reductions in serious vascular events. HPV vaccination starts in September Vaccination against human papilloma virus will be part of the national immunisation programme from the start of the new school year in September. The vaccine, administered as three doses over six months, will initially be offered to girls aged 12,13 (school year 8) to reduce their risk of cervical cancer. A two-year catch-up campaign for all girls up to 18 years old will begin in 2009. MHRA: pancreatitis with exenatide warning The incretin mimetic exenatide (Byetta), licensed for the treatment of type 2 diabetes, may rarely be associated with pancreatitis, warns the MHRA (Drug Safety Update 2008;1:Issue 10). One case has been reported in the UK and 89 in the USA and Germany. The MHRA advises that patients should be warned of the symptoms of pancreatitis (severe abdominal pain, back pain). Treatment should be discontinued if pancreatitis is suspected and the case reported on a yellow card. 2007 prescribing bill Primary-care expenditure on drugs in England in 2007 totalled £8.37 billion, only 2 per cent more than in 2006, according to the latest statistics from the Information Centre (www.ic.nhs.uk). Prescription numbers increased by almost 6 per cent. Prescribing increased in most BNF categories but changed little in musculoskeletal drugs and immunological products and vaccines. Calceos: calcium/ vitamin D3 price match Manufacturer Galen has pledged to continue to price-match its calcium/vitamin D3 supplement Calceos with Adcal-D3 or Calcichew D3 Forte. If the price of either product falls below that of Calceos chewable tablets, Galen will match it within six months. The company says it will honour the pledge until at least 2011. Copyright © 2008 Wiley Interface Ltd [source]

Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension

BRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2009
C Agard
Background and purpose:, Pulmonary arterial hypertension (PAH) is associated with increased contraction and proliferation of pulmonary vascular smooth muscle cells. The anti-diabetic drug metformin has been shown to have relaxant and anti-proliferation properties. We thus examined the effect of metformin in PAH. Experimental approach:, Metformin effects were analysed in hypoxia- and monocrotaline-induced PAH in rats. Ex vivo and in vitro analyses were performed in lungs, pulmonary artery rings and cells. Key results:, In hypoxia- and monocrotaline-induced PAH, the changes in mean pulmonary arterial pressure and right heart hypertrophy were nearly normalized by metformin treatment (100 mg·kg,1·day,1). Pulmonary arterial remodelling occurring in both experimental models of PAH was also inhibited by metformin treatment. In rats with monocrotaline-induced PAH, treatment with metformin significantly increased survival. Metformin increased endothelial nitric oxide synthase phosphorylation and decreased Rho kinase activity in pulmonary artery from rats with PAH. These effects are associated with an improvement of carbachol-induced relaxation and reduction of phenylephrine-induced contraction of pulmonary artery. In addition, metformin inhibited mitogen-activated protein kinase activation and strongly reduced pulmonary arterial cell proliferation during PAH. In vitro, metformin directly inhibited pulmonary artery smooth muscle cell growth. Conclusions and implications:, Metformin protected against PAH, regardless of the initiating stimulus. This protective effect may be related to its anti-remodelling property involving improvement of endothelial function, vasodilatory and anti-proliferative actions. As metformin is currently prescribed to treat diabetic patients, assessment of its use as a therapy against PAH in humans should be easier. [source]