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PubMed2005

Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies.

AIM: The efficacy, dose-response relationships and safety of an extended-release formulation of metformin (Glucophage) XR) were evaluated in two double-blind, randomized, placebo-controlled studies of 24 and 16 weeks' duration, in patients with inadequate glycaemic control despite diet and exercise. Protocol 1 provided an evaluation of metformin XR at a commonly used dosage. Protocol 2 evaluated different dosages of metformin XR. METHODS: In Protocol 1, 240 patients were randomized to receive metformin XR 1000 mg once daily. or placebo in a 2:1 ratio for 12 weeks (patients could receive metformin XR 1500 mg during weeks 12-24 if required). In Protocol 2, 742 patients were randomized to receive metformin XR 500 mg once daily, 1000 mg once daily, 1500 mg once daily, 2000 mg once daily, 1000 mg twice daily or placebo for 16 weeks. The primary endpoint in each study was the change from baseline in HbA(1C) at 12 weeks (Protocol 1) or 16 weeks (Protocol 2). RESULTS: Metformin XR reduced HbA(1C) in Protocol 1, with mean treatment differences for 1000 mg once daily vs. placebo of -0.7% at 12 weeks and -0.8% at 24 weeks (p < 0.001 for each). In Protocol 2, a clear dose-response relationship was evident at doses up to 1500 mg, with treatment differences vs. placebo of -0.6% (500 mg once daily), -0.7% (1000 mg once daily), -1.0% (1500 mg once daily) and -1.0% (2000 mg once daily). The efficacy of metformin XR 2000 mg once daily and 1000 mg twice daily were similar (mean treatment differences vs. placebo in HbA(1C) were -1.0% and -1.2%, respectively). More patients achieved HbA(1C) < 7.0% with metformin XR vs. placebo in Protocol 1 (29% vs. 14% at 12 weeks) and with once-daily metformin XR in Protocol 2 (up to 36% vs. 10% at 16 weeks). No significant changes in fasting insulin or body weight occurred. Total and low-density lipoprotein (LDL)-cholesterol improved (p < 0.05-p < 0.001) in metformin XR groups in Protocol 2. Metformin XR was well tolerated; gastrointestinal side effects were more common with metformin XR vs. placebo, but few patients withdrew for this reason (1.3% vs. 1.3% in Protocol 1 and 1.6% vs. 0.9% in Protocol 2). CONCLUSIONS: Once-daily metformin XR presents an effective and well-tolerated therapeutic option for delivering metformin in a convenient manner, which supports good compliance with therapy.

Adult↗
PubMed1996

Metformin: an antihyperglycemic agent for treatment of type II diabetes.

OBJECTIVE: To review the comparative efficacy of metformin, sulfonylureas, and insulin in the treatment of patients with type II diabetes. DATA SOURCES: Articles were identified by a MEDLINE search of articles from 1966 to 1994, using the terms metformin, sulfonylurea, chlorpropamide, glipizide, glyburide, tolazamide, tolbutamide, and insulin, published in English, French, or German. Articles also were identified from bibliographies of pertinent articles. STUDY SELECTION: With the exception of articles dealing with the pharmacology of metformin, only randomized, active, controlled studies were selected for review. DATA EXTRACTION: Effects of metformin therapy on metabolic and cardiovascular risk factors were abstracted: weight, blood pressure, total and low-density lipoprotein cholesterol, triglycerides, fasting and postprandial glucose, and glycosylated hemoglobin. DATA SYNTHESIS: Metformin is an antihyperglycemic agent with a mean bioavailability of 50-60%. It is eliminated primarily by renal filtration and secretion and has a half-life of approximately 6 hours in patients with type II diabetes. Although the half-life of metformin is prolonged in patients with renal impairment, no specific dosage adjustments have been recommended. This agent has no effect in the absence of insulin. Metformin is as effective as the sulfonylureas in treating patients with type II diabetes and has a more prominent postprandial effect than the sulfonylureas or insulin. When combined with a sulfonylurea, metformin has been shown to exert antihyperglycemic effects in addition to the sulfonylurea with which it is combined. Metformin decreases absorption of vitamin B12 and folic acid, although reported cases of megaloblastic anemia are rare. Cimetidine decreases the elimination of metformin; therefore, the manufacturer reccommends a reduced metformin dosage when these agents are combined. The most frequently reported adverse effects of metformin are gastrointestinal in nature (diarrhea, nausea, abdominal pain, and metallic taste, in decreasing order). Metformin has been used in Canada, Great Britain, and the rest of Europe for more than 30 years and was approved for use in the US in December 1994. CONCLUSIONS: Three trials comprise the Food and Drug Administration approval database (one foreign). Metformin will be most useful in managing patients with poorly controlled postprandial hyperglycemia, as its postprandial effect is much greater than that of the sulfonylureas. In contrast, sulfonylureas or insulin are more effective for managing patients with poorly controlled fasting hyperglycemia. Metformin should be considered a first-line agent, particularly in obese or hyperlipidemic patients.

Diabetes Mellitus, Type 2↗
PubMed2005

Metformin administration improves endothelial function in women with polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to investigate the endothelial status in young women with polycystic ovary syndrome (PCOS), using a simple and easily reproducible hemodynamic method combined with a biological marker and to evaluate the effect of metformin treatment on these parameters. DESIGN: Descriptive clinical trial. METHODS: Forty young women, 20 with PCOS and 20 normal women of similar age and body mass index were studied. Metformin (1700 mg daily) was administered for 6 months to the PCOS group. The endothelium status and the metabolic and hormonal profile were studied in both groups, as well as after metformin, by flow-mediated dilatation (FMD) on the brachial artery and by measurements of plasma endothelin-1 (ET-1) levels. RESULTS: FMD was impaired in the PCOS group when compared with controls (3.24+/-0.71% vs 8.81+/-1.07% respectively, P<0.0001), but this difference normalized after metformin treatment (PCOS(post-metformin) vs controls: 8.17+/-1.26 vs 8.81+/-1.07%, P = 0.70) since the values significantly improved after metformin treatment (PCOS(pre-metformin) vs PCOS(post-metformin): 3.24+/-0.71 vs 8.17+/-1.26%, P=0.003). ET-1 levels were significantly higher in the PCOS women compared with the control group (7.23+/-0.50 vs 4.99+/-0.69 fmol/l, P=0.01), they improved significantly after metformin treatment (PCOS(pre-metformin) vs PCOS(post-metformin): 7.23+/-0.50 vs 3.57+/-0.60 fmol/l, P<0.0001) and their difference compared with the control group was reversed (PCOS(post-metformin) vs controls: 3.57+/-0.60 vs 4.99+/-0.69 fmol/l, P=0.13). Metformin administration improved hyperandrogenemia. However, in this study, mathematical methods used to assess insulin resistance failed to show any detected alteration after treatment with metformin. CONCLUSIONS: PCOS women were found to exhibit endothelial dysfunction compared with controls, which was reversed 6 months after metformin administration.

Adult↗
PubMed2026

OCT1 Variants Are Associated with Metformin Clearance and Gluconeogenesis: Mechanistic Insights for Youth-Onset Type 2 Diabetes in the MIGHTY Study.

AIMS/HYPOTHESIS: Behavioral and phenotypic characteristics do not fully explain variability in African Americans with youth-onset type 2 diabetes (Y-T2D) treated with metformin with or without liraglutide. We hypothesized that biological heterogeneity, including genetic variation in the metformin transporter OCT1, influences metformin pharmacokinetics and hepatic glucose flux. Therefore, we sought to characterize metformin pharmacokinetics in Y-T2D and evaluate genetic variants known to modulate metformin efficacy in adults to determine the mechanisms underlying variation in treatment response. METHODS: We evaluated genetic variants related to metformin transport and mechanisms of action in 30 Y-T2D using a candidate-gene approach to evaluate the association of pharmacogenetic variants with fasting glucose and gluconeogenesis. In a subset of Y-T2D randomized to 3 months of metformin (n=11) or metformin and liraglutide (n=8), we constructed a metformin population pharmacokinetic model and evaluated gene variant associations. RESULTS: A one-compartment first-order absorption and elimination pharmacokinetic model provided the optimal fit. Metformin pharmacokinetic parameters were similar by group and not related to glycemia. The rs628031_OCT1 A allele was associated with greater metformin clearance. The rs622342_OCT1 C allele was associated with lower post-treatment fractional gluconeogenesis (&#x3b2; [95% CI] = -8.8 [-14.13, -3.47] %, Adjusted R2 = 0.56, P = 0.003). The rs7903146_TCF7L2 T allele was associated with greater reductions in fasting glucose among those treated with metformin + liraglutide (&#x3b2; = -1.32 [-2.42, -0.22] mmol/L, Adjusted R2 = 0.8, P<0.002), but baseline glucose and gluconeogenesis (P<0.0001) were the strongest predictors of post-treatment glycemia. CONCLUSION/INTERPRETATION: In Y-T2D, OCT1 gene variants rs628031 and rs622342 were associated with metformin clearance and gluconeogenesis, respectively. TCF7L2 variant rs7903146 may contribute to differences in glycemic response in youth treated with metformin and liraglutide. These findings suggest genetic variants may be important for understanding variable metformin response in Y-T2D.

SLC22A1↗
PubMed2000

Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial.

CONTEXT: Most antidiabetic agents target only 1 of several underlying causes of diabetes. The complementary actions of the antidiabetic agents metformin hydrochloride and rosiglitazone maleate may maintain optimal glycemic control in patients with type 2 diabetes; therefore, their combined use may be indicated for patients whose diabetes is poorly controlled by metformin alone. OBJECTIVE: To evaluate the efficacy of metformin-rosiglitazone therapy in patients whose type 2 diabetes is inadequately controlled with metformin alone. DESIGN: Randomized, double-blind, placebo-controlled trial from April 1997 and March 1998. SETTING: Thirty-six outpatient centers in the United States. PATIENTS: Three hundred forty-eight patients aged 40 to 80 years with a mean fasting plasma glucose level of 12.0 mmol/L (216 mg/dL), a mean glycosylated hemoglobin level of 8.8%, and a mean body mass index of 30.1 kg/m2 were randomized. INTERVENTIONS: Patients were assigned to receive 2.5 g/d of metformin plus placebo (n = 116); 2.5 g/d of metformin plus 4 mg/d of rosiglitazone (n = 119); or 2.5 g/d of metformin and 8 mg/d of rosiglitazone (n = 113) for 26 weeks. MAIN OUTCOME MEASURES: Glycosylated hemoglobin levels, fasting plasma glucose levels, insulin sensitivity, and beta-cell function, compared between baseline and week 26, by treatment group. RESULTS: Glycosylated hemoglobin levels, fasting plasma glucose levels, insulin sensitivity, and beta-cell function improved significantly with metformin-rosiglitazone therapy in a dose-dependent manner. The mean levels of glycosylated hemoglobin decreased by 1.0% in the 4 mg/d metformin-rosiglitazone group and by 1.2% in the 8 mg/d metformin-rosiglitazone group and fasting plasma glucose levels by 2.2 mmol/L (39.8 mg/dL) and 2.9 mmol/L (52.9 mg/dL) compared with the metformin-placebo group (P<.001 for all). Of patients receiving 8 mg/d of metformin-rosiglitazone, 28.1% achieved a glycosylated hemoglobin level of 7% or less [corrected]. Dose-dependent increases in body weight and total and low-density lipoprotein cholesterol levels were observed (P<.001 for both rosiglitazone groups vs placebo). The proportion of patients reporting adverse experiences was comparable across all groups. CONCLUSIONS: Our data suggest that combination treatment with once-daily metformin-rosiglitazone improves glycemic control, insulin sensitivity, and beta-cell function more effectively than treatment with metformin alone.

Adult↗
PubMed2005

Metformin reduces blood pressure and restores endothelial function in aorta of streptozotocin-induced diabetic rats.

Effect of metformin treatment on blood pressure, endothelial function and oxidative stress in streptozotocin (STZ)-induced diabetes in rats was studied. In vitro effect of metformin on vascular reactivity to various agonist in the presence of metformin in untreated nondiabetic and STZ-diabetic rats were also studied. Sprague-Dawley rats were randomized into nondiabetic and STZ-diabetic groups. Rats were further randomized to receive metformin (150 mg/kg) or vehicle for 4 weeks. Metformin treatment reduced blood pressure without having any significant effect on blood glucose level in STZ-diabetic rats. Enhanced phenylephrine (PE)-induced contraction and impaired acetylcholine (Ach)-induced relaxation in STZ-diabetic rats were restored to normal by metformin treatment. Enhanced Ach-induced relaxation in metformin-treated STZ-diabetic rats was blocked due to pretreatment with 100 microM of Nomega-nitro-L-arginine-methyl ester (L-NAME) or 10 microM of methylene blue but not 10 microM of indomethacin. Metformin treatment significantly increased antioxidant enzymes and reduced lipid peroxidation in STZ-diabetic rats. In vitro studies in aortic rings of untreated nondiabetic and STZ-diabetic rats showed that the presence of higher concentration of metformin (1 mM and 10 mM) significantly reduced PE-induced contraction and increased Ach-induced relaxation. Metformin per se relaxed precontracted aortic rings of untreated nondiabetic and STZ-diabetic rats in a dose-dependent manner. Pretreatment with L-NAME or removal of endothelium blocked metformin-induced relaxation at lower concentration (up to 30 microM) but not at higher concentration (above 30 microM). Metformin-induced relaxation was blocked in the presence of 1 mM of 4-aminopyridine, or 1 mM of tetraethylammonium but not in the presence of 100 microM of barium ion or 10 microM of glybenclamide. The restored endothelial function along with direct effect of metformin on aortic rings and reduced oxidative stress contributes to reduced blood pressure in STZ-diabetic rats. From the present study, it can be concluded that metformin administration to STZ-diabetic rats lowers blood pressure, and restores endothelial function.

4-Aminopyridine↗
PubMed2006

[Traditional contraindications to the use of metformin -- more harmful than beneficial?].

For fear of lactic acidosis the currently listed contraindications to the use of metformin exclude a large number of people with type 2 diabetes from efficacious anti-hyperglycemic and cardioprotective treatment. Yet recent data call the traditional contraindications to metformin into question. As the incidence of lactic acidosis in patients with type 2 diabetes is the same with or without metformin therapy (about 9 per 100,000 patient years) there is no evidence that metformin therapy is associated with an increased risk of lactic acidosis. Similarly, despite disregard internationally of major metformin contraindications, there has been no corresponding increase in the incidence of lactic acidosis. Metformin treatment of elderly diabetics with multiple comorbidities and explicit contraindications has led to significantly better clinical parameters in them than in the control group without metformin; and there were no cases of lactic acidosis. The two groups did not differ with regard to progression of renal failure, patient-oriented endpoints or overall mortality. Compared with its predecessors phenformin and buformin, metformin is considerably less lipophilic and has a shorter plasma half-life; it is eliminated renally in unchanged form. In type 2 diabetics treated with metformin -- even those over 70 years of age and those in mild renal failure -- no relevant increases in lactate levels were found. In patients with lactic acidosis there was no correlation between the levels of metformin and lactate. The prognosis of lactic acidosis is determined less by the serum concentrations of metformin and lactate than by the hypoxia caused by the underlying disease and comorbidities. These findings raise doubts about the significance of metformin in the pathogenesis of lactic acidosis. On the basis of the current data, advanced age per se, mild renal impairment and stable heart failure can no longer be upheld as contraindications to the use of metformin. It should be safe to withdraw metformin the evening before radiological examinations with intravenous contrast media or surgical procedures under general anaesthesia in diabetics with normal renal function.

Acidosis, Lactic↗
PubMed2005

The beneficial effects of insulin and metformin on in vitro developmental potential of porcine oocytes and embryos.

To investigate whether insulin and/or metformin improve the developmental competence of porcine oocytes and embryos, insulin (100 ng/ml) and/or metformin (10(-5) M) were supplemented during in vitro maturation (IVM) and/or in vitro culture (IVC) periods. Insulin (33 to 34% vs. 21%) or insulin plus metformin (27 to 39% vs. 21%) significantly (P < 0.01) increased the rates of blastocyst formation, whereas metformin alone had no effect when added during the first half (0-22 h), the latter half (22-44 h), or the entire (0-44 h) maturation period. No additional effect of insulin plus metformin on increasing blastocyst formation was observed compared to insulin alone. When supplemented during IVC, insulin (34% vs. 23%) or insulin plus metformin (35% vs. 23%) significantly (P < 0.05) increased the rates of blastocyst formation, whereas metformin alone had no effect. Compared to insulin alone, no additional effect of insulin plus metformin on increasing blastocyst formation was observed. When added during the entire IVM and IVC, insulin (40% vs. 24%) or insulin plus metformin (52% vs. 21%) significantly increased the rates of blastocyst formation, whereas metformin alone had no effect. In addition, the effect of insulin was enhanced when supplemented with metformin compared to insulin alone (52% vs. 40%). After IVM, oocyte glutathione (GSH) content and tyrosine kinase activity were measured. Insulin significantly (P < 0.01) increased oocyte GSH content (6.2 pmol vs. 4.3 pmol) and metformin significantly (P < 0.01) enhanced the action of insulin on GSH content (7.3 pmol vs. 6.2 pmol) and tyrosine kinase activity (1.9 arbitrary units [AU] vs. 1.5 AU) when compared to insulin alone. In conclusion, insulin increased the developmental potential of porcine oocytes and embryos, and metformin enhanced the action of insulin when supplemented during the entire IVM and IVC. The effects of insulin and metformin were associated with oocyte GSH content and tyrosine kinase activity.

Animals↗
PubMed1992

Characterization of metformin transport system in NIH 3T3 cells.

The biochemical properties of the metformin transport system were studied in NIH 3T3 cells. 14C-metformin uptake appeared to be a sodium dependent process. Iso-osmotical replacement of Na+ by choline chloride in the assay medium resulted in a decrease of metformin uptake. Amiloride (200 microM) inhibited the metformin transport by 35% in these cells. Gramicidin, a channel ionophore, was the most effective in inhibiting the metformin transport as compared to valinomycin, a mobile ion carrier, and Ca2+ ionophore (A 23187). Loading of cells with asparagine, ornithine, or polylysine did not influence the uptake process. However, the addition of lysine or arginine significantly stimulated the metformin uptake by NIH 3T3 cells. Similarly, the addition of metformin stimulated the arginine uptake by these cells, suggesting that metformin shares the y+ transport system. Metformin inhibited competitively the uptake of 14C-spermidine, a molecule of the polyamine family, by NIH 3T3 cells, whereas the latter failed to influence the uptake of the former significantly by these cells. Incubation of NIH 3T3 cells in the presence of difluoromethyl-ornithine (a suicidal inhibitor of polyamine biosynthesis) stimulated the spermidine, but not the metformin, uptake by these cells. Interestingly, a prolonged incubation of these cells in the presence of metformin failed to down-regulate the spermidine transport process. The spermidine- and methylglyoxal-bis(guanylhydrazone), MGBG-transport deficient (3T3MG) cells which do not accumulate exogeneous spermidine or MGBG, took up 14C-metformin. However, 14C-metformin uptake by 3T3MG cells was lower than that by normal NIH 3T3 cells.

3T3 Cells↗
PubMed2000

Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors.

Nearly 30% of patients treated with metformin experience gastrointestinal side effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether metformin induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy specimens of human duodenal mucosa, metformin (1, 10, and 30 microM) caused an increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak increases in 5-HT outflow were observed after 10-15 min exposure to metformin, returning to baseline levels after 25 min. Tetrodotoxin (1 microM) reduced by about 50% the metformin-evoked increase in 5-HT outflow (P<0.05). Metformin-evoked release was not affected by scopolamine + hexamethonium, propranolol, the 5-HT3 receptor antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the presence of tetrodotoxin (1 microM), somatostatin (1 microM) further reduced metformin-induced 5-HT release by 15-20%. In view of the 5-HT releasing effects of selective 5-HT3 receptor agonists to which metformin (N-N-dimethylbiguanide) is structurally related, we investigated whether metformin directly interacts with 5-HT3 receptors. Receptor binding (inhibition of [3H]-GR65630 binding) and agonist effects (stimulation of [14C]-guanidinium influx) at 5-HT3 receptors were studied in murine neuroblastoma N1E-115 cells, which express functional 5-HT3 receptors. Metformin up to 0.3 mM failed to inhibit [3H]-GR65630 binding and to modify displacement of [3H]-GR65630 binding induced by 5-HT. 5-HT (3 microM) stimulated the influx of [14C]-guanidinium in intact N1E-115 cells. Metformin up to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ substance P-induced influx of [14C]-guanidinium. Our results indicate that metformin induces 5-HT3 receptor-independent release of 5-HT from human duodenal mucosa via neuronal and non-neuronal mechanisms. Part of the gastrointestinal side effects observed during treatment with metformin could, thus, be produced by the release of 5-HT and other neurotransmitter substances within the duodenal mucosa.

Animals↗
PubMed1999

Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome.

In 43 amenorrheic women with polycystic ovary syndrome (PCOS), 31 (74%) with fasting hyperinsulinemia (> or =20 microU/mL), our aim was to determine whether Metformin (Bristol-Myers Squibb, Princeton, NJ), which reduces hyperinsulinemia, would reverse the endocrinopathy of PCOS, allowing resumption of regular normal menses. A second aim was to assess the effects of weight loss versus other Metformin-induced effects on ovarian function, and to determine if there were different responses to Metformin between those who lost weight and those who did not. A third aim was to assess associations between PCOS, 4G/5G polymorphism in the promoter sequence of the plasminogen activator inhibitor-1 gene (PAI-1 gene), and PAI activity (PAI-Fx). Of the 43 women, 40 (93%) had normal fasting blood glucose and 37 had normal hemoglobin A1C (HgA1C); onlythree (7%) had type 2 diabetes mellitus. Metformin (1.5 to 2.25 g/d) was given for 6.1+/-5.1 months (range, 1.5 to 24), to 16 patients for less than 3 months, to 12 for 3 to 6 months, and to 15 for at least 6 months. On Metformin, 39 of 43 patients (91%) resumed normal menses. The percentage of women resuming normal menses did not differ among treatment duration groups (P<.1) or among dose groups (P>.1). The body mass index (BMI) decreased from 36.4 + 7 Kg/m2 at study entry to 35.1+/-6.7 on Metformin (P=.0008). Of 43 patients, 28 (67%) lost weight (1 to 69 pounds), with nine (21%) losing at least 12 pounds. On Metformin, the median fasting serum insulin decreased from 26 microU/mL to 22 (P=.019), testosterone decreased from 61 ng/dL to 47 (P=.003), and estradiol increased from 41 pg/mL to 71 (P=.0001). Metformin-induced improvements in ovarian function were independent of weight loss (testosterone decrease, P<.002; estradiol increase, P<.0004). The change in response variables on Metformin did not differ (P>.05) between those who lost weight and those who did not, excepting Lp(a), which increased 4 mg/dL in those who lost weight and decreased 9 mg/dL in those who did not (P = .003). The change in response variables on Metformin did not differ among the five quintiles of weight loss, excepting fasting glucose (P<.05), which increased 6 mg/dL in those who lost the least weight on Metformin versus those in the 60th to 80th percentile for weight loss, in whom glucose decreased 33 mg/dL. Although the pretreatment fasting serum insulin was not significantly correlated with testosterone (r=.24, P=.13) or androstenedione (r=.27, P=.09), on Metformin, the change in insulin correlated positively with the change in testosterone (r=.35, P=.047) and with the change in androstenedione (r=.48, P=.01). Patients were more likely than normal controls (83% v 64%, P=.016) to be heterozygous or homozygous for 4G polymorphism of the PAI-1 gene and were also more likely to have high PAI-Fx (> or =22 U/mL, 28% v3%, chi(2)=10.1, P=.001). Metformin reduces the endocrinopathy of PCOS, allowing resumption of normal menses in most (91%) previously amenorrheic women with PCOS.

Adult↗
PubMed2001

Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients.

AIM: To compare the effect of glimepiride in combination with metformin with monotherapy of each drug on glycaemic control in Type 2 diabetic patients. DESIGN AND METHODS: Randomized, double-blind, double-dummy, parallel-group multicentre study conducted in France. Type 2 diabetic patients aged 35-70 years inadequately controlled by metformin monotherapy 2550 mg daily for at least 4 weeks were randomized to either metformin, glimepiride or metformin and glimepiride. RESULTS: Three hundred and seventy-two patients aged 56 +/- 8 years were treated for 5 months. Combination treatment was significantly more efficient in controlling HbA1c (% change + 0.07 +/- 1.20 for metformin, + 0.27 +/- 1.10 for glimepiride, -0.74 +/- 0.96 for combination treatment, P < 0.001), fasting blood glucose (FBG) (mmol/l change + 0.8 +/- 0.4 for metformin, + 0.7 +/- 3.1 for glimepiride and -1.8 +/- 2.2 for combination treatment, P < 0.001) and post-prandial blood glucose (PPBG) (mmol/l change + 1.1 +/- 5.9 for metformin, + 0.1 +/- 5.1 for glimepiride and -2.6 +/- 3.9 for combination treatment, P < 0.001) than either glimepiride or metformin alone. There was no significant difference between metformin or glimepiride monotherapy with respect to the change in HbA1c or FBG; however, glimepiride was significantly more effective than metformin in reducing PPBG. The incidence of symptomatic hypoglycaemia was higher in the combination group than in either monotherapy group (P = 0.039). CONCLUSIONS: Addition of glimepiride to metformin in Type 2 diabetic patients inadequately controlled by metformin alone resulted in superior glycaemic control compared with glimepiride or metformin monotherapy.

Adult↗
PubMed2000

Metformin improves vascular function in insulin-resistant rats.

This study assessed the effect of metformin treatment on insulin, mean arterial pressure (MAP), and endothelial function in insulin-resistant (IR) rats. In addition, we assessed the direct effect of metformin in vitro. Sprague-Dawley rats were randomized to control (n=28) or IR (n=28) groups. Rats were further randomized to receive metformin (300 mg/kg) or placebo for 2 weeks. MAP and insulin were measured. Subsequently, a third-order branch of the superior mesenteric artery was isolated, and endothelial function was assessed. Specifically, dose-response experiments of acetylcholine (ACh) with or without N-nitro-L-arginine (LNNA) were performed. For in vitro experiments, mesenteric arteries were removed from untreated control and IR rats and treated with metformin (100 micromol/L) before ACh+/-LNNA. MAP and insulin levels were improved in IR-metformin compared with IR-placebo rats. Maximal relaxation (E(max)) to ACh was enhanced in IR-metformin (92+/-2%) compared with IR-placebo rats (44+/-4%) (P<0.05). Relaxation in response to ACh+LNNA was greater in IR-metformin (33+/-4%) than in IR-placebo rats (12+/-4%) but remained depressed compared with control rats (E(max)=68+/-5%). The control group was not affected by metformin. In vitro treatment of arteries with metformin in response to ACh produced results similar to those in the experiments with metformin-treated rats. Although metformin improves metabolic abnormality in IR rats, this action does not appear to mediate its effect on vascular function. Both in vivo and in vitro metformin improved ACh-induced relaxation in IR rats to control levels, apparently through nitric oxide-dependent relaxation. These data suggest that metformin improves vascular function through a direct mechanism rather than by improving metabolic abnormalities.

Acetylcholine↗
PubMed1996

Clinical pharmacokinetics of metformin.

The biguanide metformin (dimethylbiguanide) is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus (NIDDM). Considerable renewal of interest in this drug has been observed in recent years. Metformin can be determined in biological fluids by various methods, mainly using high performance liquid chromatography, which allows pharmacokinetic studies in healthy volunteers and diabetic patients. Metformin disposition is apparently unaffected by the presence of diabetes and only slightly affected by the use of different oral formulations. Metformin has an absolute oral bioavailability of 40 to 60%, and gastrointestinal absorption is apparently complete within 6 hours of ingestion. An inverse relationship was observed between the dose ingested and the relative absorption with therapeutic doses ranging from 0.5 to 1.5 g, suggesting the involvement of an active, saturable absorption process. Metformin is rapidly distributed following absorption and does not bind to plasma proteins. No metabolites or conjugates of metformin have been identified. The absence of liver metabolism clearly differentiates the pharmacokinetics of metformin from that of other biguanides, such as phenformin. Metformin undergoes renal excretion and has a mean plasma elimination half-life after oral administration of between 4.0 and 8.7 hours. This elimination is prolonged in patients with renal impairment and correlates with creatinine clearance. There are only scarce data on the relationship between plasma metformin concentrations and metabolic effects. Therapeutic levels may be 0.5 to 1.0 mg/L in the fasting state and 1 to 2 mg/L after a meal, but monitoring has little clinical value except when lactic acidosis is suspected or present. Indeed, when lactic acidosis occurs in metformin-treated patients, early determination of the metformin plasma concentration appears to be the best criterion for assessing the involvement of the drug in this acute condition. After confirmation of the diagnosis, treatment should rapidly involve forced diuresis or haemodialysis, both of which favour rapid elimination of the drug. Although serious, lactic acidosis due to metformin is rare and may be minimised by strict adherence to prescribing guidelines and contraindications, particularly the presence of renal failure. Finally, only very few drug interactions have been described with metformin in healthy volunteers. Plasma levels may be reduced by guar gum and alpha-glucosidase inhibitors and increased by cimetidine, but no data are yet available in the diabetic population.

Administration, Oral↗
PubMed2005

Long-term treatment with rosiglitazone and metformin reduces the extent of, but does not prevent, islet amyloid deposition in mice expressing the gene for human islet amyloid polypeptide.

Islet amyloid deposition in type 2 diabetes is associated with reduced beta-cell mass. Therefore, interventions aimed at reducing islet amyloid formation may help preserve beta-cell mass in type 2 diabetes. Rosiglitazone and metformin act by different mechanisms to improve insulin sensitivity and thereby reduce beta-cell secretory demand, resulting in decreased release of insulin and islet amyloid polypeptide (IAPP), the unique constituent of islet amyloid deposits. We hypothesized that this reduced beta-cell secretory demand would lead to reduced islet amyloid formation. Human IAPP (hIAPP) transgenic mice, a model of islet amyloid, were treated for 12 months with rosiglitazone (1.5 mg.kg(-1).day(-1), n = 19), metformin (1 g.kg(-1).day(-1), n = 18), or control (n = 17). At the end of the study, islet amyloid prevalence (percent islets containing amyloid) and severity (percent islet area occupied by amyloid), islet mass, beta-cell mass, and insulin release were determined. Islet amyloid prevalence (44 +/- 8, 13 +/- 4, and 11 +/- 3% for control, metformin-, and rosiglitazone-treated mice, respectively) and severity (9.2 +/- 3.0, 0.22 +/- 0.11, and 0.10 +/- 0.05% for control, metformin-, and rosiglitazone-treated mice, respectively) were markedly reduced with both rosiglitazone (P < 0.001 for both measures) and metformin treatment (P < 0.001 for both measures). Both treatments were associated with reduced insulin release assessed as the acute insulin response to intravenous glucose (2,189 +/- 857, 621 +/- 256, and 14 +/- 158 pmol/l for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin vs. control and P < 0.005 for rosiglitazone vs. control), consistent with reduced secretory demand. Similarly, islet mass (33.4 +/- 7.0, 16.6 +/- 3.6, and 12.2 +/- 2.1 mg for control, metformin-, and rosiglitazone-treated mice, respectively) was not different with metformin treatment (P = 0.06 vs. control) but was significantly lower with rosiglitazone treatment (P < 0.05 vs. control). When the decreased islet mass was accounted for, the islet amyloid-related decrease in beta-cell mass (percent beta-cell mass/islet mass) was ameliorated in both rosiglitazone- and metformin-treated animals (57.9 +/- 3.1, 64.7 +/- 1.4, and 66.1 +/- 1.6% for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin or rosiglitazone vs. control). In summary, rosiglitazone and metformin protect beta-cells from the deleterious effects of islet amyloid, and this effect may contribute to the ability of these treatments to alleviate the progressive loss of beta-cell mass and function in type 2 diabetes.

Amyloid↗
PubMedDate not supplied

Treatment of non-insulin-dependent diabetes mellitus with metformin.

BACKGROUND: Metformin alleviates hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM) by inhibiting hepatic glucose production and improving peripheral insulin sensitivity. In contrast to sulfonylureas, metformin does not stimulate insulin-secretion, promote weight gain, exacerbate hyperinsulinemia, or cause hypoglycemia. It also favorably affects serum lipids. METHODS: A comprehensive review of the medical literature from 1968 to the present was conducted using the key words "metformin" and "non-insulin-dependent diabetes mellitus." RESULTS: Metformin monotherapy was superior to placebo and comparable to sulfonylureas in reducing fasting plasma glucose and glycosylated hemoglobin levels in patients with NIDDM uncontrolled by diet. Metformin and sulfonylureas, however, had diverse effects on body weight and fasting plasma insulin levels; both weight and insulin levels remained unchanged or decreased with metformin and increased with sulfonylureas. In patients with secondary sulfonylurea failure, the combination of metformin and a sulfonylurea synergistically improved glycemic control better than either drug alone and was comparable to insulin plus sulfonylurea. When hyperglycemia is uncontrolled by insulin after secondary sulfonylurea failure, limited data suggest the efficacy of metformin plus insulin. The mild, transient, self-limited gastrointestinal side effects that sometimes occur can be minimized by gradually increasing the doses and by taking metformin with food. Risk of metformin-associated lactic acidosis is low if prescribing guidelines are adhered to. Potential adverse drug interactions include hypoglycemia during concurrent sulfonylurea therapy and elevated metformin plasma concentrations when metformin is taken concomitantly with cimetidine. CONCLUSIONS: Metformin can be used safely and effectively as first-line monotherapy in NIDDM or in combination with a sulfonylurea when monotherapy with either agent fails. It can be particularly suitable when weight gain, hyperlipidemia, and hypoglycemia are clinically important issues.

Acidosis, Lactic↗
PubMed1998

Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes.

Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3x3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity.

Adult↗
PubMed2000

Intensive insulin therapy combined with metformin in obese type 2 diabetic patients.

Unlike other pharmacological therapies used in obese type 2 diabetic patients, metformin has been shown to improve glycemic control with lower insulin levels and not to involve weight gain. We therefore examined the effect of adjunct metformin in 13 severely obese type 2 diabetic patients (BMI 39.3 +/- 3.9 kg/m2) in suboptimal glycemic control pretreated with intensified insulin therapy. Patients were randomly assigned to either metformin or placebo treatment (double-blind) for 10 weeks and after a 2 week washout period received the opposite treatment, respectively, for 10 additional weeks. HbA1c decreased comparably during placebo (from 8.1 +/- 0.4 to 7.6 +/- 0.3%) and metformin (from 8.5 +/- 0.4 to 7.4 +/- 0.3%, p = 0.29 vs. placebo). Changes in fasting glucose levels were also not different between placebo (from 9.3 +/- 0.7 to 9.5 +/- 0.7 mM) and metformin (from 10.3 +/- 0.5 to 9.5 +/- 0.6 mM, p = 0.44 vs. placebo). Total exogenous insulin requirements decreased from 53 +/- 10 to 35 +/- 7 units during metformin treatment (p = 0.02 vs. placebo). Changes in fasting insulin levels during placebo and metformin treatments were not different (p = 0.11). Metformin had no effect on body weight and serum triglycerides but marginally decreased serum cholesterol levels (from 239 +/- 18 to 211 +/- 14 mg/dl, p = 0.005, p = 0.08 vs. placebo). During the oral glucose tolerance test no differences were observed in the areas under the curve for glucose and insulin while that for C-peptide showed a tendency to increase during metformin administration. We conclude that addition of metformin to insulin treatment in severely obese type 2 diabetic patients improves glycemia but not hyperinsulinemia in comparison to intensive insulin therapy alone. With adjunct metformin, approximately 30% less exogenous insulin is required. With respect to glycemia and lipids, adjunct metformin can be a reasonable treatment alternative in selected obese patients with type 2 diabetes already on intensive insulin therapy.

Body Mass Index↗