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PubMed2002

[Effects of metformin on the plasminogen activator system, endocrine, metabolic profiles in patients with polycystic ovary syndrome and clomiphene resistant cases].

OBJECTIVE: To assess the therapeutic effects of metformin in patients with polycystic ovary syndrome (PCOS) and clomiphene (CC) resistant cases. METHODS: Thirty one patients with PCOS, including 8 CC resistant cases were studied. Serum tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), menstrual and reproductive hormone patterns, lipid and glucose metabolic parameters, bilateral ovarian volume, side effects were determined before and after oral administration of metformin 375 mg three times daily for 12 - 16 weeks. Metformin and CC were co-administered in CC resistant cases who had not restored their menstrual cycle after the treatment with metformin alone for investigating ovulation rate. In the remaining non-CC resistant metformin failure cases the dosage of metformin was incrersed to 500 mg three times daily for investigating menstrual cycle. RESULTS: After administration of metformin for 12 - 16 weeks, serum PAI-1, luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio, androstenedione, testosterone, low density liproprotein-cholesterol, total cholesterol, fasting insulin concentration and response to oral glucose tolerant test (OGTT), diastolic blood pressure decreased significantly, while FSH and estradiol levels increased, bilateral ovarian volume shrunk significantly (P < 0.05 - 0.01). Body mass index, waist hip ratio, LH, tPA, systolic blood pressure, prolactin, fasting glucose concentration and response to OGTT, high density liproprotein-cholesterol, apoliprotein A, apoliprotein B, triglycerides levels did not change significantly (P > 0.05). Nineteen out of thirty one cases (61%) had restoration of menstrual cycle, 2 became pregnant. In 6 CC resistant cases who had not restoration of menstrual cycle after the treatment with metformin, CC induced ovulation in 12/18 cycles or 5/6 cases and 2 pregnancies achieved. In others 6 metformin failure cases the dosage of metformin was increased to 500 mg three times daily, one restored menstrual cycle and became pregnant. CONCLUSIONS: Metformin may ameliorate the PAI-1, endocrine, metabolic profiles and menstrual abnormalities and improve the ovarian response to CC in CC resistant cases. Metformin provides a safe and effective approach to the treatment of PCOS.

Adult↗
PubMed1990

Diurnal pattern of plasma metformin concentrations and its relation to metabolic effects in type 2 (non-insulin-dependent) diabetic patients.

The authors describe the diurnal profile of plasma metformin concentrations in a group of 6 Type 2 (noninsulin-dependent) diabetic patients studied at two different daily metformin doses (500 mg and 850 mg b.d.) and report data on the relationships between plasma metformin and metabolic effects over a 14 h period. In addition, the effect of circulating metformin on insulin binding to isolated monocytes has been evaluated. At the two different daily doses fasting plasma metformin concentrations were similar (3.23 +/- 0.35 mumol/l and 3.86 +/- 0.72 mumol/l, mean values +/- SEM, at low and high dose respectively). Drug peak values and averaged concentrations (4.66 +/- 0.39 mumol/l vs 6.35 +/- 0.69 mumol/l) were significantly higher when more drug was administered. Mean plasma glucose was lower when 1,700 mg/day instead of 1,000 mg/day of metformin was given (7.3 +/- 0.4 mmol/l vs 9.1 +/- 0.9 mmol/l, p less than 0.05). After dosing, at higher plasma metformin concentrations corresponded lower plasma glucose values. The averaged blood lactate levels resulted 1.46 +/- 0.4 mmol/l (p less than 0.05 vs matched diet treated diabetic patients) at the higher drug dose. A significant positive correlation emerged between mean plasma metformin concentrations and mean blood lactate levels (r: 0.76, p less than 0.02). Alanine, glycerol and B-OH-butyrate levels were similar at the two metformin daily doses, and were not correlated to plasma metformin. The binding of insulin to isolated human monocytes was similar in metformin-treated diabetic patients (4.48 +/- 0.45) as in healthy volunteers (4.62 +/- 0.34); insulin binding was correlated (p less than 0.05) with plasma metformin levels.

Alanine↗
PubMed2002

Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy.

BACKGROUND: The risk of lactic acidosis during metformin therapy is linked to specific and well-documented conditions that constitute contraindications or precautions to use of the agent. We conducted a retrospective evaluation of metformin use to determine whether prescribing practices are in accord with published contraindications and precautions. METHODS: All patients admitted to the hospital during a 6-month period who received at least 1 dose of metformin were identified through hospital pharmacy records. Patient demographics and clinical characteristics were then evaluated to determine whether metformin was prescribed to patients possessing any of the risk factors associated with development of lactic acidosis. RESULTS: We identified 263 hospitalizations involving 204 patients who received at least 1 dose of metformin during inpatient admission. Patients had at least 1 absolute contraindication to metformin therapy in 71 admissions (27%). In 29 (41%) of these 71 admissions, treatment with metformin continued despite the contraindication. The most common contraindication, elevated serum creatinine concentration, was present or developed during 32 admissions (12%); however, metformin use was appropriately discontinued in only 8 (25%) of these 32 patients. Of the precautions against metformin use, concomitant administration of cationic agents was the most common, occurring in 97 admissions (37%). CONCLUSIONS: Many patients are treated with metformin despite having clinical conditions that place them at risk for developing lactic acidosis. To minimize this risk, it is essential that prescribers develop a better understanding of the prescribing guidelines for metformin.

Acidosis, Lactic↗
PubMed2006

Risk factors of vitamin B(12) deficiency in patients receiving metformin.

BACKGROUND: Identification of risk factors for metformin-related vitamin B(12) deficiency has major potential implications regarding the management of diabetes mellitus. METHODS: We conducted a nested case-control study from a database in which the source population consisted of subjects who had levels of both serum vitamin B(12) and hemoglobin A(1c) checked in a central laboratory. We identified 155 cases of diabetes mellitus and vitamin B(12) deficiency secondary to metformin treatment. Another 310 controls were selected from the cohort who did not have vitamin B(12) deficiency while taking metformin. RESULTS: A total of 155 patients with metformin-related vitamin B(12) deficiency (mean +/- SD serum vitamin B(12) concentration, 148.6 +/- 40.4 pg/mL [110 +/- 30 pmol/L]) were compared with 310 matched controls (466.1 +/- 330.4 pg/mL [344 +/- 244 pmol/L]). After adjusting for confounders, we found clinically important and statistically significant association of vitamin B(12) deficiency with dose and duration of metformin use. Each 1-g/d metformin dose increment conferred an odds ratio of 2.88 (95% confidence interval, 2.15-3.87) for developing vitamin B(12) deficiency (P<.001). Among those using metformin for 3 years or more, the adjusted odds ratio was 2.39 (95% confidence interval, 1.46-3.91) (P = .001) compared with those receiving metformin for less than 3 years. After exclusion of 113 subjects with borderline vitamin B(12) concentration, dose of metformin remained the strongest independent predictor of vitamin B(12) deficiency. CONCLUSIONS: Our results indicate an increased risk of vitamin B(12) deficiency associated with current dose and duration of metformin use despite adjustment for many potential confounders. The risk factors identified have implications for planning screening or prevention strategies in metformin-treated patients.

Age Factors↗
PubMed1996

Effect of metformin on intact proinsulin and des 31,32 proinsulin concentrations in subjects with non-insulin-dependent (type 2) diabetes mellitus.

We have investigated the effects of metformin treatment on concentrations of proinsulin-like molecules in subjects with Type 2 (non-insulin-dependent) diabetes mellitus. Metformin was given for 12 weeks in an increasing dose up to 850 mg three times daily in a double-blind placebo-controlled cross-over design to 27 subjects (age 53.0 +/- 9.9 years; 19 male, 8 female). Concentrations of insulin and proinsulin-like molecules were measured by highly specific enzymoimmunometric assays. The end of metformin treatment was compared with end of placebo treatment. Metformin lowered fasting plasma glucose concentrations (at 12 weeks, metformin: 8.0 +/- 2.5 vs placebo: 12.0 +/- 2.3 mmol l-1, p r2 0.001;). Concentrations of intact (median change -2.9 (range -28.4 to +2.5 pmol l-1), p = 0.02) and des 31,32 proinsulin (median change -1.6 (range -14.1 to +5.4 pmol l-1), p = 0.07) and percentage of proinsulin-like molecules were reduced by metformin treatment (median change -6% (range -16% to +6%), p = 0.02). Changes in the ratio of proinsulin-like molecules were significantly related with those in fasting plasma glucose (r1 = 0.69, p < 0.001). Changes in concentrations of intact and des 31,32 proinsulin on metformin were not related to changes in body mass index or fasting glucose concentration or changes in concentrations of total triglyceride, cholesterol, and plasminogen activator inhibitor-1. Therefore, metformin treatment in subjects with Type 2 diabetes mellitus significantly reduced concentrations of proinsulin-like molecules over a 12-week period. However, these changes were not related to changes in cardiovascular risk factors seen during metformin treatment. We conclude that short-term effects of metformin treatment on proinsulin-like molecules are similar to those previously observed with dietary treatment in subjects with Type 2 diabetes but opposite to those of sulphonylurea treatment. The effect of long-term treatment with metformin on proinsulin-like molecules needs to be assessed.

Blood Glucose↗
PubMed2005

Metformin monotherapy for type 2 diabetes mellitus.

BACKGROUND: Metformin is an anti-hyperglycaemic agent used for the treatment of type 2 diabetes mellitus. Type 2 diabetes may present long-term complications: micro- (retinopathy, nephropathy and neuropathy) and macrovascular (stroke, myocardial infarction and peripheral vascular disease). Two meta-analyses have been published before, although only secondary outcomes were assessed. OBJECTIVES: To assess the effects of metformin monotherapy on mortality, morbidity, quality of life, glycaemic control, body weight, lipid levels, blood pressure, insulinaemia, and albuminuria in patients with type 2 diabetes mellitus. SEARCH STRATEGY: Studies were obtained from computerised searches of multiple electronic databases and hand searches of reference lists of relevant trials identified. Date of last search: September 2003. SELECTION CRITERIA: Trials fulfilling the following inclusion criteria: Diabetes mellitus type 2, metformin versus any other oral intervention, assessment of relevant clinical outcome measures, use of random allocation. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data, using a standard data extraction form. Data were summarised under a random effects model. Dichotomous data were expressed as relative risk. We calculated the risk difference (RD), and the Number Needed to Treat, when it was possible. We collected data of mean and standard deviation from changes to baseline. However many trials reported end point data. This limitation lead to the expression of the results as standardised mean differences (SMD) and an overall SMD was calculated. Heterogeneity was tested for using the Z score and the I-squared statistic. Subgroup, sensitivity analysis and meta-regression were used to explore heterogeneity. MAIN RESULTS: We included for analysis 29 trials with 37 arms (5259 participants), comparing metformin (37 arms and 2007 participants) with sulphonylureas (13 and 1167), placebo (12 and 702), diet (three and 493), thiazolidinediones (three and 132), insulin (two and 439), meglitinides (two and 208), and glucosidase inhibitors (two and 111). Nine studies reported data on primary outcomes. Obese patients allocated to intensive blood glucose control with metformin showed a greater benefit than chlorpropamide, glibenclamide, or insulin for any diabetes-related outcomes (P = 0.009), and for all-cause mortality (P = 0.03). Obese participants assigned to intensive blood glucose control with metformin showed a greater benefit than overweight patients on conventional treatment for any diabetes-related outcomes (P = 0.004), diabetes-related death (P = 0.03), all-cause mortality (P = 0.01), and myocardial infarction (P = 0.02). Patients assigned to metformin monotherapy showed a significant benefit for glycaemia control, weight, dyslipidaemia, and diastolic blood pressure. Metformin presents a strong benefit for HbA1c when compared with placebo and diet; and a moderated benefit for: glycaemia control, LDL cholesterol, and BMI or weight when compared with sulphonylureas. AUTHORS' CONCLUSIONS: Metformin may be the first therapeutic option in the diabetes mellitus type 2 with overweight or obesity, as it may prevent some vascular complications, and mortality. Metformin produces beneficial changes in glycaemia control, and moderated in weight, lipids, insulinaemia and diastolic blood pressure. Sulphonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, insulin, and diet fail to show more benefit for glycaemia control, body weight, or lipids, than metformin.

Diabetes Mellitus, Type 2↗
PubMed2002

Metformin restores responses to insulin but not to growth hormone in Sprague-Dawley rats.

Administration of growth hormone (GH) increases muscle mass in F344 x BN rats, but not in Sprague-Dawley (S-D) rats. S-D rats are insulin-resistant and insulin responsiveness is required for the anabolic actions of GH. We hypothesized that correction of insulin resistance with metformin might also restore anabolic effects of GH. Treatment with GH (0.25 or 1.0 mg/kg twice daily for 9 days) had limited anabolic effects, reducing weight gain by 14%, increasing muscle glycogen content by 40% and increasing exercise capacity by 24%, but failing to increase muscle mass or to reduce fat mass. GH also impaired insulin responsiveness and increased visceral fat TNF content of visceral fat by 77%. Metformin enhanced insulin responsiveness in skeletal muscle, but failed to enhance anabolic effects of GH. Rats aged 14 weeks were treated for 21 days with metformin (320 mg/kg/day) and for the last 9 days, with GH (0.25 mg/kg, twice daily). Metformin caused a 2.3-fold increase in insulin-stimulated muscle glucose transport and a 20% reduction in muscle fatty acid oxidation, indicating increased glucose utilization. However, metformin did not augment GH-induced weight reduction. Metformin decreased visceral fat by 22% and subcutaneous fat by 20%, but no decreases were observed in the GH/metformin group. GH increased muscle glycogen by 40%, but the effect was reversed by metformin. VO(2max) was increased 24% by GH and 17% by metformin, but was not elevated in the GH/metformin group. GH increased TNF in visceral fat and the effect was augmented by metformin (144% increase). We conclude that metformin enhances some aspects of insulin responsiveness, but does not enhance anabolic responses to GH. The latter may, in part, be explained by the failure of metformin to prevent GH-induced elevation of TNF in visceral fat.

Adipose Tissue↗
PubMed2005

Metformin transport by renal basolateral organic cation transporter hOCT2.

PURPOSE: Metformin, an antihyperglycemic agent, is eliminated by tubular secretion in addition to glomerular filtration in the human kidney. This study was performed to characterize metformin transport by human organic cation transporter 2 (hOCT2), the most abundant organic cation transporter in the basolateral membranes of the human kidney. METHODS: Accumulation of [14C]metformin was assessed by the tracer experiments in the human embryonic kidney (HEK293) cells expressing hOCT2. RESULTS: The transport of [14C]metformin was markedly stimulated in hOCT2-expressing cells compared with the vector-transfected cells. The accumulation of [14C]metformin was concentrative and was dependent on the membrane potential, showing consistency with the characteristics of hOCT2. The apparent Km and Vmax values of [14C]metformin transport by hOCT2-expressing HEK293 cells were 1.38+/-0.21 mM and 11.9+/-1.5 nmol mg protein(-1) min(-1), respectively. The order of the potencies of unlabeled biguanides to inhibit [14C]metformin transport by hOCT2 was phenformin > buformin > metformin. Furthermore, [14C]metformin transport was inhibited slightly or moderately by cationic drugs such as procainamide and quinidine at respective therapeutic concentrations. CONCLUSIONS: Metformin is transported by the basolateral organic cation transporter hOCT2 in the human kidney. hOCT2 could play a role in the drug interactions between metformin and some cationic drugs.

Biological Transport↗
PubMed1996

Vascular effects of metformin. Possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat.

Metformin, an antidiabetic agent, potentiates insulin action and reduces insulin resistance. We examined the antihypertensive effects and vascular effects of metformin in spontaneously hypertensive rats (SHR). Wistar-Kyoto normotensive (WKY) and SHR were injected with metformin (100 mg/kg) or saline subcutaneously twice daily for 4 weeks. Blood pressure was recorded by a tail-cuff plethesmographic method. Metformin treatment significantly attenuated (P < .05) the increase in blood pressure in metformin treated SHR versus untreated control SHR. At the end of the experimental period of 4 weeks, metformin-treated SHR had a mean blood pressure that was 34 mm lower than that of untreated SHR. Metformin treatment had no significant effect on blood pressure in WKY rats. Treatment of SHR aortic smooth muscle (SM) cells with metformin (2 micrograms/mL) for 24 h significantly decreased (P < .05) arginine vasopressin- and thrombin- stimulated increase in [Ca2+]i. However, metformin treatment did not have a significant effect on the basal [Ca+]i. Incubation of SHR aortic SM cells with OH-L-arginine (25 to 100 mumol/L) for 24 h increased nitrite production in a dose dependent manner. Metformin (5 micrograms/mL) treatment of SM cells increased nitrite production at all concentrations of OH-L-arginine; however, differences were significant (P < .05) only at 25 and 50 mumol/L OH-L-arginine. These results suggest that metformin may be decreasing arterial pressure in the SHR, at least in part, by attenuating the agonist-stimulated [Ca2+]i response in SHR vascular smooth muscle cells.

Animals↗
PubMed2001

Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study.

OBJECTIVE: To determine whether metformin would safely reduce the rate of first-trimester spontaneous abortion without teratogenicity in 19 women with the polycystic ovary syndrome (PCOS). DESIGN: Prospective pilot study. SETTING: Outpatient. PATIENT(S): Twenty-two previously oligoamenorrheic, nondiabetic women with PCOS; 125 women with PCOS who were not currently pregnant and who had > or = 1 previous pregnancy while they were not receiving metformin. INTERVENTION(S): Metformin, 1.5-2.55 g/day, throughout pregnancy. MAIN OUTCOME MEASURE(S): Rates of first-trimester spontaneous abortion and teratogenicity. RESULT(S): Before metformin, 10 women had 22 previous pregnancies with 16 first-trimester spontaneous abortions (73%). While receiving metformin, these 10 women had 6 normal live births (60%), 1 spontaneous abortion (10%), and 3 normal ongoing pregnancies (30%) (all > or = 13 weeks; median gestation, 23 weeks). Among women receiving metformin, including those with live births and normal pregnancy for at least the first trimester, 1 of 10 (10%) had first-trimester spontaneous abortion compared with 73% in 22 previous pregnancies without metformin (P<.002). To date, the 19 women receiving metformin have had no adverse maternal side effects, and no birth defects have occurred; 9 (47%) had normal term live births, 2 (11%) had normal and appropriate for gestational age births (one at 33 and one at 35 weeks), 6 (32%) have ongoing normal pregnancies lasting longer than the first trimester, and 2 (10.5%) had first-trimester spontaneous abortions. Sonography showed normal fetal development without congenital defects in the 6 ongoing pregnancies (median gestation, 23 weeks). Among women who received metformin before conception, reductions in insulin and plasminogen activator inhibitor activity were correlated (r=0.65, P=.04). CONCLUSION(S): Metformin therapy throughout pregnancy in women with PCOS reduces the otherwise high rate of first-trimester spontaneous abortion seen among women not receiving metformin and does not appear to be teratogenic.

Abnormalities, Drug-Induced↗
PubMed2000

Effect of altered gastric emptying and gastrointestinal motility on metformin absorption.

AIMS: The purpose of this in vivo human study was to assess the effect of altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects. METHODS: An open-label, three treatment, three period crossover study was conducted in 11 healthy volunteers. Each subject received 550 mg metformin hydrochloride in solution alone; 5 min after a 10 mg i.v. dose of metoclopramide; and 30 min after a 30 mg oral dose of propantheline. Metformin solution was radiolabeled by the addition of 99mTc-DTPA. The gastrointestinal transit of the solution was monitored by gamma scintigraphy and the pharmacokinetic data were correlated with the scintigraphic findings. RESULTS: Scintigraphic data indicated that pretreatment with metoclopramide decreased gastric emptying time and increased gastrointestinal motility while pretreatment with propantheline had the opposite effect. The systemic disposition of metformin was not altered by pretreatment with metoclopramide and propantheline, as judged by unchanged renal clearance and elimination half-life of metformin. Extent of metformin absorption was essentially unchanged after pretreatment with metoclopramide. However, AUC(0,infinity) and % UR (percent dose excreted unchanged in urine) generally increased with increase in gastric emptying time and small intestinal transit times. GI overlay plots showed that the absorption phase of metformin plasma profile always coincided with gastric emptying and the beginning of decline of metformin plasma concentrations was usually associated with the colon arrival. Only in cases where the intestinal transit was drastically prolonged by propantheline pretreatment, was a decline in plasma levels observed prior to colon arrival. CONCLUSIONS: Metformin is primarily absorbed from the small intestine. The extent of metformin absorption is improved when the gastrointestinal motility is slowed. These findings have significant implications in the design of a metformin modified release dosage form.

Adult↗
PubMed2001

Contraindications to metformin therapy in patients with Type 2 diabetes--a population-based study of adherence to prescribing guidelines.

AIMS: To define the number of people in Tayside, Scotland (population 349 303) with Type 2 diabetes who use metformin, the incidence of contraindications to its continued use in these people and the proportion that discontinued metformin treatment following the development of a contraindication. METHODS: Retrospective cohort study of the incidence of contraindications to metformin in all patients with Type 2 diabetes using metformin from January 1993 to June 1995. The contraindications of acute myocardial infarction, cardiac failure, renal impairment and chronic liver disease were identified by: the regional diabetes information system, biochemistry database and hospital admissions database and a database of all encashed community prescriptions. RESULTS: One thousand eight hundred and forty seven subjects (26.3% of those with Type 2 diabetes) redeemed prescriptions for metformin. Of these, 3.5% were admitted with an acute myocardial infarction (71 episodes); 4.2% were admitted with cardiac failure (114 episodes); 21.0% received metformin and loop diuretics for cardiac failure concurrently; 4.8% developed renal impairment; and 2.8% developed chronic liver disease. The development of contraindications rarely resulted in discontinuation of metformin, for example only 17.5% and 25% stopped metformin after admission with acute myocardial infarction and development of renal impairment, respectively. In total, 24.5% of subjects receiving metformin, 6.4% of all people with Type 2 diabetes, had contraindications to its use. There was one episode of lactic acidosis in 4600 patient years. CONCLUSIONS: This population-based study shows that 24.5% of patients prescribed metformin have contraindications to its use. Development of contraindications rarely results in discontinuation of metformin therapy. Despite this, lactic acidosis remains rare. Diabet. Med. 18, 483-488 (2001)

Cohort Studies↗
PubMed2000

Metformin treatment corrects vascular insulin resistance in hypertension.

OBJECTIVE: In states of insulin resistance, the vasorelaxant actions of insulin are blunted, which may contribute towards the development of increased vascular tone/hypertension and reduced glucose uptake. To examine whether treating insulin resistance in hypertension restores the vascular actions of insulin, we studied the long-term effects of metformin on the contractile responses of isolated aortas from control and insulin-resistant, hyperinsulinaemic fructose-hypertensive rats in the presence and absence of insulin. DESIGN AND METHODS: Sprague Dawley rats were divided into control, control metformin-treated, fructose and fructose metformin-treated groups (n = 8 per group). The treated groups received metformin (500 mg/kg per day for 6 weeks), following which isometric responses to noradrenaline (NA) and angiotensin II (A-II) were examined in thoracic aortas in the presence and absence of insulin (100 mU/ml for 2 h) using isolated organ-bath apparatus. In addition, endothelium-dependent and independent vascular responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were also studied. RESULTS: Metformin treatment prevented the development of fructose-induced insulin resistance, hyperinsulinaemia and hypertension. Insulin attenuated the contractile responses to NA and A-II in control rat aortas; however, blood vessels from untreated fructose rats were refractory to insulin-induced vasodilation. Strikingly, long-term metformin treatment restored the vasodepressor actions of insulin in fructose rats. Metformin did not affect the contractile responses to NA or A-II in either control or fructose rats. In addition, metformin treatment restored ACh-induced endothelium-dependent vasorelaxation in aortas from fructose rats without affecting SNP-induced relaxation. CONCLUSIONS: These data show, for the first time, that long-term metformin treatment corrects vascular insulin resistance and improves endothelium-dependent vasorelaxation in hypertension. These effects appear to be secondary to metformin-induced improvements in metabolic derangements (versus a direct vascular action of metformin). Improving the vascular effects of insulin may serve to decrease peripheral tone, attenuate blood pressure and improve insulin sensitivity.

Acetylcholine↗
PubMed2006

Biphasic insulin aspart 30 plus metformin: an effective combination in type 2 diabetes.

AIM: This study compared glycaemic control achieved with biphasic insulin aspart 30 (BIAsp 30) monotherapy, BIAsp 30 plus metformin and glibenclamide plus metformin in patients with type 2 diabetes not adequately controlled with metformin. METHODS: In this multinational, open-labelled, parallel group, 16-week trial, 341 patients (patients not adequately controlled with metformin for at least 1 month) with type 2 diabetes were studied. Patients were randomized to receive BIAsp 30, twice daily (n = 107 exposed to treatment), or BIAsp 30, twice daily, plus metformin (n = 108) or glibenclamide plus metformin (n = 114). The primary endpoint was HbA(1c) at end of trial; adverse events, hypoglycaemia episodes, blood lipids and weight were also monitored. RESULTS: In the total population (HbA(1c) 7.5-13.0% at screening), end-of-trial HbA(1c) levels were lower in patients receiving BIAsp 30 plus metformin compared with those receiving BIAsp 30 only [mean treatment difference (+/-s.e.m), 0.39 +/- 0.15%, p = 0.007]. In a subpopulation (HbA(1c) > or = 9.0% at baseline, n = 193), patients receiving BIAsp 30 plus metformin had significantly lower HbA(1c) levels at the end of the trial compared with those receiving glibenclamide plus metformin (treatment difference, 0.46 +/- 0.21%, p = 0.027). Mean body weight (+/-s.d) at the end of the trial was significantly lower in patients receiving glibenclamide plus metformin compared with those receiving BIAsp 30 only (84.3 +/- 13.3 kg vs. 88.9 +/- 16.9 kg, p < 0.001). No major hypoglycaemic episodes were recorded during the trial, and incidence rates for minor and symptoms-only hypoglycaemia were low and similar between treatment groups (0.03-0.04 events/patient/week). CONCLUSION: BIAsp 30 added to metformin could be an appropriate therapeutic option for achieving good glycaemic control, compared with the addition of a second oral agent, particularly where HbA(1c) > or = 9%.

Biphasic Insulins↗
PubMed1999

Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats.

Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130+/-3 mm Hg; metformin, 133+/-5 mm Hg; mean+/-SEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153+/-4 mm Hg; metformin, 140+/-5 mm Hg; P<0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136+/-13 mm Hg) than those in the control (98+/-5 mm Hg, P<0.01), metformin (100+/-7 mm Hg, P<0.01), and metformin/high-salt groups (92+/-3 mm Hg, P<0.01). Finally, metformin lowered heart rate in rats that ate the normal- and high-salt diets (310+/-3 and 305+/-4 bpm) compared with rats that ate normal- and high-salt diets given vehicle (332+/-3 and 324+/-2 bpm, P<0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet.

Animals↗
PubMed1996

Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus.

This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects received 4 single-blind single-dose treatments of metformin HCL (850 mg, 1,700 mg, 2,550 mg, and placebo) and a multiple-dose treatment of 850 mg metformin HCL (3 times daily for 19 doses). After each single-dose treatment and the final dose of the multiple-dose phase, multiple plasma and urine samples were collected for 48 hours and assayed for metformin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared with women, or during multiple-dose treatment versus single-dose treatment. Plasma concentrations of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700-mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concentrations and do not influence insulin concentrations. With multiple doses, both preprandial and postprandial glucose concentrations and preprandial insulin concentrations were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the average fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.

Adult↗
PubMed2006

A fixed-dose combination of pioglitazone and metformin: A promising alternative in metabolic control.

BACKGROUND: When type 2 diabetes is managed with glucose-lowering monotherapy, glycemic control ultimately deteriorates due to the inability of the beta-cell to overcome insulin resistance. Combining drugs with different complementary mechanisms of action improves long-term glycemic control and may lower the risk of vascular complications. A fixed-dose combination of pioglitazone (a thiazolidinedione) and metformin has been approved for use in the US (Actoplus met) and in Europe (Competact). SCOPE: This review (based upon MEDLINE and EMBASE searches from January 1990 to April 2006) discusses the potential benefits of co-formulating metformin and pioglitazone with respect to compliance and targeting glycemia, as well as other metabolic parameters. FINDINGS: Pioglitazone increases insulin sensitivity, while metformin reduces hepatic gluconeogenesis and improves peripheral glucose uptake. Both agents reduce hyperglycemia and hyperinsulinemia, and appear to protect beta-cell function. Their similar pharmacokinetic time profiles have facilitated a co-formulation bioequivalent to their separate administration. In randomized studies, pioglitazone and metformin administered separately provided significantly better glycemic control than metformin monotherapy or metformin plus gliclazide. Pioglitazone and metformin have complimentary benefits on diabetic dyslipidemia; pioglitazone primarily improves high-density lipoprotein cholesterol and triglyceride levels (to a greater extent than rosiglitazone does), while metformin mainly improves total cholesterol. Pioglitazone and metformin also modulate other atherosclerosis biomarkers, including inflammatory mediators, coagulation thrombosis components, and carotid intima media thickness. Together, these pleiotropic effects have the potential to confer a reduced risk of cardiovascular disease in patients with type 2 diabetes. Pioglitazone and metformin are well tolerated in combination, with low rates of hypoglycemia, and the convenience of a single tablet may be expected to aid dosing compliance. CONCLUSION: The co-formulation of pioglitazone and metformin is a rational approach that maximizes the established, complimentary benefits of these agents, while potentially improving compliance.

Cardiovascular Diseases↗
PubMed1996

The antidiabetic drug metformin elevates receptor tyrosine kinase activity and inositol 1,4,5-trisphosphate mass in Xenopus oocytes.

Although metformin is an important antidiabetic, its mechanism of action is still unknown. To study its mechanism, we examined metformin stimulation of insulin action on the Xenopus oocyte. Similar to therapeutic concentrations, maximal stimulation of insulin-induced meiotic cell division was achieved at about 1-10 microg/ml (or 7.7-77 /microM) metformin. An equivalent concentration of metformin was required to elevate receptor tyrosine kinase activity (in whole cells or a membrane-cortex preparation) and, through this tyrosine kinase activation, inositol 1,4,5-trisphosphate (IP3) production. With whole cells, the preincubation time for metformin stimulation of insulin action (approximately 1 h) was equivalent to the time required for metformin to maximize tyrosine phosphorylation and raise IP3, levels. With the membrane-cortex preparation, metformin was active within minutes; thus, metformin may act at an intracellular site. Since metformin can increase IP3, mass, we prevented elevation of calcium by prior microinjection of a calcium chelator or heparin (a drug that inhibits IP3 binding to the IP3 receptor). Both the chelator and heparin blocked metformin stimulation of insulin action on whole cells. Since microinjection of IP3, also stimulates insulin action, metformin may stimulate insulin action by elevation of intracellular calcium in addition to activation of the receptor tyrosine kinase.

Animals↗