Metformin (Adimet)

Metformin is a medicine used in the treatment and control of type II diabetes mellitus. It is an antihypoglycemic agent which manages the levels of blood glucose by decreasing glucose production by the liver. It activates a certain insulin receptor which in turn decreases insulin secretion and increases insulin sensitivity. Metformin helps the body to respond more efficiently to the insulin which already exists, but it does not work in type I diabetes, because there is no insulin to work with. However, Metformin is efficient enough to be used alone in a blood sugar monitoring therapy. Since Metformin does not directly decrease blood sugar levels, side effects associated with hypoglycemia are unlikely to occur, but they can and a doctor has to be contacted immediately if they do. Recent research has found that metformin can also be beneficial for the treatment of polycystic ovarian syndrome.

J Clin Endocrinol Metab. 2005 May 10;
Metformin and weight loss in obese women with polycystic ovary syndrome (PCOS): comparison of doses.
Harborne LR, Sattar N, Norman JE, Fleming R.
University Departments of Obstet. Gynecology and Vascular Biochemistry, Level 3 (Level 4) Q.E.B., Royal Infirmary, Glasgow G31 2ER, UK.

Context: metformin treatment of women with polycystic ovary syndrome (PCOS) is widespread, following studies with diverse patient populations. No comparative examination of weight changes or metabolite responses to different doses has been reported. Objective: to determine whether different doses of metformin (1500 or 2550 mg per day) would have different effects upon body weight, circulating hormones, markers of inflammation and lipid profiles. Design: prospective cohorts randomized to 2 doses of metformin. Setting: university teaching hospital with patients from gynaecology / endocrinology clinics Patients: obese (Ob, BMI 30 to <37; n = 42) and morbidly obese (Mob, BMI >/=37; n = 41) women with PCOS. Intervention: patients were randomized to 2 doses of metformin, and parameters assessed after 4 and 8 months. Main Outcome Measures: changes in body mass, circulating hormones, markers of inflammation and lipid profiles. Results. Intention to treat analyses showed significant weight loss in both dose groups. Only the Ob sub-group showed a dose relationship (1.5 Kg and 3.6 Kg in 1500 mg and 2550 mg groups respectively, P = 0.04). The Mob group showed similar reductions (3.9 and 3.8 Kg) in both groups. Suppression of androstenedione was significant with both metformin doses, but with no clear dose relationship. Generally beneficial changes in lipid profiles were not related to dose. Conclusion. Weight loss is a feature of protracted metformin therapy in obese women with PCOS, with greater weight reduction potentially achievable with higher doses. Further studies are required to determine whether other aspects of the disorder may benefit from the higher dose of metformin.

Diabetes Nutr Metab. 2004 Dec;17(6):336-42.
Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without Type 2 diabetes.
Mannucci E, Tesi F, Bardini G, Ognibene A, Petracca MG, Ciani S, Pezzatini A, Brogi M, Dicembrini I, Cremasco F, Messeri G, Rotella CM.
Section of Diabetology, Geriatric Unit, Department of Critical Care, University of Florence, Italy.

Metformin has been shown to increase glucagon-like peptide-1 (GLP-1) levels after an oral glucose load in obese non-diabetic subjects. In order to verify if this effect of the drug was also present in obese Type 2 diabetic patients who have never been treated with hypoglycemic drugs, 22 Type 2 diabetic and 12 matched non-diabetic obese patients were studied. GLP-1 was measured before and after a 100 g glucose load at baseline, after a single oral dose of 850 mg of metformin, and after 4 weeks of treatment with metformin 850 mg three times daily. Post-load GLP-1 levels were significantly lower in diabetic patients. A single dose of metformin did not modify GLP-1 levels. After 4 weeks of treatment, fasting GLP-1 increased in diabetic patients (3.8 vs 4.9 pmol/l; p<0.05), while the incremental area under the curve of GLP-1 significantly increased in both diabetic [93.6 (45.6-163.2) vs 151.2 (36.0-300.5) pmol x min/l; p<0.05] and non-diabetic [187.2 (149.4-571.8) vs 324.0 (238.2-744.0) pmol x min/l; p<0.05] subjects. In conclusion, GLP-1 levels after an oral glucose load in obese type 2 diabetic patients were increased by 4 weeks of metformin treatment in a similar fashion as in obese subjects with normal glucose tolerance.

Diabetologia. 2005 May 12;
Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes.
Charbonnel B, Schernthaner G, Brunetti P, Matthews DR, Urquhart R, Tan MH, Hanefeld M.
Endocrinology Clinic, Hotel Dieu, Place Alexis Ricordeau, 44093, Nantes Cedex 1, France, Bernard.Charbonnel@univ-nantes.fr.

AIMS/HYPOTHESIS: The aim of this analysis was to examine the long-term effects of pioglitazone or gliclazide addition to failing metformin monotherapy and pioglitazone or metformin addition to failing sulphonylurea monotherapy in patients with type 2 diabetes. METHODS: Two 2-year, randomised, multicentre trials were performed in patients with inadequately controlled type 2 diabetes (HbA(1)c 7.5-11% inclusive), who were receiving either metformin or a sulphonylurea at >/=50% of the maximum recommended dose or at the maximum tolerated dose. In the first study, patients on metformin received add-on therapy with pioglitazone (15-45 mg/day, n=317) or gliclazide (80-320 mg/day, n=313). In the second study, patients on sulphonylurea therapy were randomised to receive add-on therapy with either pioglitazone (15-45 mg/day, n=319) or metformin (850-2,550 mg/day, n=320). HbA(1)c, fasting plasma glucose, insulin and lipids were investigated. RESULTS: At week 104, the mean reduction from baseline in HbA(1)c was 0.89% for pioglitazone and 0.77% for gliclazide addition to metformin (p=0.200). There was a statistically significant between-group difference for the change in mean fasting plasma glucose at week 104 (-1.8 mmol/l for pioglitazone vs -1.1 mmol/l for gliclazide, p<0.001). There were no significant differences in changes from baseline in glycaemic parameters for pioglitazone compared with metformin addition to sulphonylurea therapy. Whether added to metformin or sulphonylurea, pioglitazone caused significantly greater decreases in triglycerides and significantly greater increases in HDL cholesterol than the comparator regimens (p</=0.001). There were decreases in LDL cholesterol in the comparator groups and these were significantly different from the small changes observed with pioglitazone (p<0.001). All treatment regimens were well tolerated. There were weight increases of 2.5 kg and 3.7 kg in the pioglitazone and 1.2 kg in the gliclazide add-on groups, and there was a mean decrease of 1.7 kg in the metformin add-on group. CONCLUSIONS/INTERPRETATION: As add-on therapy to existing sulphonylurea or metformin therapy, pioglitazone improved glycaemic control and this improvement was sustained over 2 years. Furthermore, there were potential benefits in terms of improvements in specific lipid abnormalities. This could offer an advantage over the addition of other oral agents in the long-term treatment of diabetes.

Metabolism. 2005 Mar;54(3):314-20.
The effects of rosiglitazone and metformin on the plasma concentrations of resistin in patients with type 2 diabetes mellitus.
Jung HS, Youn BS, Cho YM, Yu KY, Park HJ, Shin CS, Kim SY, Lee HK, Park KS.

Abstract Resistin is a protein secreted from adipose tissue that is thought to play a role in insulin sensitivity. We examined the effects of rosiglitazone and metformin on the plasma resistin levels in individuals with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus who showed poor glycemic control with glimepiride (4 mg/d) were randomized to rosiglitazone (4 mg/d) and metformin (500 mg bid) treatment groups. All subjects continued glimepiride treatment as well. The plasma concentrations of resistin were measured at baseline and at 6 months of treatment for both groups. The anthropometric parameters, fasting plasma glucose, HbA1c, total cholesterol, triglyceride, high-density lipoprotein cholesterol, free fatty acids, and adiponectin concentrations were also measured. After 6 months of treatment, the reduction in plasma glucose levels was similar between the 2 groups. There were no significant changes in the lipid profiles of either group during the study period. The plasma resistin levels decreased in the rosiglitazone group (2.49 +/- 1.93 vs 1.95 +/- 1.59 ng/ml; P < .05) but increased in the metformin group (2.61 +/- 1.69 vs 5.13 +/- 2.81 ng/ml; P < .05). The plasma adiponectin concentrations were increased in the rosiglitazone group (2.91 +/- 1.46 vs 4.23 +/- 1.77 mu g/ml; P < .05) but were unchanged in the metformin group. In summary, rosiglitazone treatment decreased the plasma resistin levels whereas metformin treatment increased them in patients with type 2 diabetes mellitus showing poor glycemic control with sulfonylurea therapy. These results suggest that the observed changes in plasma resistin levels are not the consequences of improved insulin resistance, nor are they consequences of glycemic control. Considering the potential role of resistin in insulin resistance, decrease in resistin levels may contribute to improving insulin action with rosiglitazone treatment.

Obstet Gynecol Surv. 2005 Mar;60(3):178-9.
Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity.
Baillargeon JP, Jakubowicz DJ, Iuomo MJ, Jakubowicz S, Nestler JE.
Hospital de Clinicas Caracas, Caracas, Venezuela; and the Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.

The goal of this randomized, controlled, double-blind trial was to learn whether insulin-sensitizing drugs can improve ovulation frequency and serum-free testosterone (T) in nonobese women with polycystic ovary syndrome (PCOS) whose insulin sensitivity was normal. The 100 women enrolled in the study, 17 to 40 years of age, had normal glucose tolerance, fasting insulin, and peak insulin levels during oral glucose tolerance testing (OGTT). The fasting glucose-to-insulin ratio also was normal. Criteria for PCOS were 8 or fewer menstrual periods in the past year and a serum total T exceeding 70 ng/dL. Participants received 850 mg metformin, 4 mg rosiglitazone, a combination of both treatments, or at least 1 placebo twice a day for 6 months. Treatment began when the women were in the equivalent of the follicular phase of the cycle.Only women given rosiglitazone gained significant body weight (1.1 kg), and the posttreatment body mass index was significantly greater in this group. All actively treated women had a significant decline in their waist-to-hip ratio. Systolic blood pressure fell significantly in all actively treated groups but not in placebo recipients. Diastolic pressure decreased and was similar in all groups at the end of the study. Ovulatory cycles were 6- to 8-fold more frequent with treatment and were highest in women given metformin or combination therapy. Ovulation rates at 6 months were markedly increased except in the placebo group. Menstrual bleeding also was greater in treated women. Combination treatment did not yield additive results for either ovulation or menstrual bleeding. Serum total and free T levels decreased significantly with active treatment. Compared with placebo, fasting insulin levels, the area under the insulin curve during an OGTT, and the OGTT-based insulin sensitivity index improved significantly after metformin or combination therapy, but not after rosiglitazone.The investigators concluded that insulin-sensitizing drugs are effective in nonobese women with PCOS even if baseline insulin sensitivity is normal.

Ann Intern Med. 2005 Mar 1;142(5):323-32.
The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance.
Herman WH, Hoerger TJ, Brandle M, Hicks K, Sorensen S, Zhang P, Hamman RF, Ackermann RT, Engelgau MM, Ratner RE; Diabetes Prevention Program Research Group.
University of Michigan Health System, Ann Arbor, Michigan, USA.

BACKGROUND: The Diabetes Prevention Program (DPP) demonstrated that interventions can delay or prevent the development of type 2 diabetes. OBJECTIVE: To estimate the lifetime cost-utility of the DPP interventions. DESIGN: Markov simulation model to estimate progression of disease, costs, and quality of life. DATA SOURCES: The DPP and published reports. TARGET POPULATION: Members of the DPP cohort 25 years of age or older with impaired glucose tolerance. TIME HORIZON: Lifetime. PERSPECTIVES: Health system and societal. INTERVENTIONS: Intensive lifestyle, metformin, and placebo interventions as implemented in the DPP. OUTCOME MEASURES: Cumulative incidence of diabetes, microvascular and neuropathic complications, cardiovascular complications, survival, direct medical and direct nonmedical costs, quality-adjusted life-years (QALYs), and cost per QALY. RESULTS OF BASE-CASE ANALYSIS: Compared with the placebo intervention, the lifestyle and metformin interventions were estimated to delay the development of type 2 diabetes by 11 and 3 years, respectively, and to reduce the absolute incidence of diabetes by 20% and 8%, respectively. The cumulative incidence of microvascular, neuropathic, and cardiovascular complications were reduced and survival was improved by 0.5 and 0.2 years. Compared with the placebo intervention, the cost per QALY was approximately 1100 dollars for the lifestyle intervention and $31 300 for the metformin intervention. From a societal perspective, the interventions cost approximately 8800 dollars and 29,900 dollars per QALY, respectively. From both perspectives, the lifestyle intervention dominated the metformin intervention. RESULTS OF SENSITIVITY ANALYSIS: Cost-effectiveness improved when the interventions were implemented as they might be in routine clinical practice. The lifestyle intervention was cost-effective in all age groups. The metformin intervention did not represent good use of resources for persons older than 65 years of age. LIMITATIONS: Simulation results depend on the accuracy of the underlying assumptions, including participant adherence. CONCLUSIONS: Health policy should promote diabetes prevention in high-risk individuals.

Biochem Biophys Res Commun. 2004 Nov 5;324(1):92-7.
Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments.
Lenhard JM, Croom DK, Minnick DT.
Department of Metabolic Diseases, GlaxoSmithKline Inc., Research Triangle Park, NC 27709, USA.
Dipeptidyl peptidase-IV (DPP-IV) regulates metabolism by degrading incretins involved in nutritional regulation. Metformin and pioglitazone improve insulin sensitivity whereas glyburide promotes insulin secretion. Zucker diabetic rats were treated with these antidiabetic agents for 2 weeks and DPP-IV activity and expression were determined. Serum DPP-IV activity increased whereas tissue activity decreased as the rats aged. Treatment of rats with metformin, pioglitazone, and glyburide did not alter DPP-IV mRNA expression in liver or kidney. Metformin and pioglitazone significantly (P<0.05) reduced serum DPP-IV activity and glycosylated hemoglobin. Glyburide did not lower DPP-IV activity or glycosylated hemoglobin. Regression analysis showed serum DPP-IV activity correlated with glycosylated hemoglobin (r=0.92) and glucagon-like peptide-1 levels (r=-0.49). Metformin, pioglitazone, and glyburide had no effect on serum DPP-IV activity in vitro, indicating these are not competitive DPP-IV inhibitors. We propose the in vivo inhibitory effects observed with metformin and pioglitazone on serum DPP-IV activity results from reduced DPP-IV secretion.

Curr Treat Options Neurol. 2004 Nov;6(6):443-450.
Type 2 Diabetes Mellitus and Insulin Resistance: Stroke Prevention and Management.
Kernan WN, Inzucchi SE.
Department of Medicine, Yale University School of Medicine, P.O. Box 208025, New Haven, CT 06520, USA. Walter.Kernan@yale.edu.
Clinically recognized disorders of glucose metabolism include impaired fasting glucose, impaired glucose tolerance (both termed prediabetes), and diabetes mellitus. Type 2 diabetes mellitus affects 6% to 13% of adults in the United States. Among patients with recent stroke, 70% will have known diabetes, occult diabetes (detectable on an oral glucose tolerance test), or prediabetes. Type 2 diabetes mellitus is associated with a two- to six-fold increased risk for first or recurrent ischemic stroke. The mechanisms for the association are myriad and include the effects of hyperglycemia on vascular tissues and coagulation, and aberrations in blood pressure regulation, lipid metabolism, endothelial function, vascular inflammation, lipid metabolism, smooth muscle cell proliferation, and fibrinolysis. The most effective strategies to prevent stroke among people with diabetes include blood pressure control, antiplatelet therapy, and statin therapy. Tight glycemic control is recommended to prevent microvascular disease, but the effect on macrovascular disease, including stroke, has not been proven. Target blood pressure should be less than 130/80. Antiplatelet therapy may be accomplished with 81 to 325 mg of aspirin daily or 75 mg of clopidogrel daily. Statins should be given in dosages effective to reduce low-density lipoprotein cholesterol to less than 100 mg/dL. For glycemic control, first line therapy for most patients is metformin, starting at 500 mg daily. With time, most patients will need two or three oral medications from different classes and many eventually will require insulin therapy. Prevention of diabetes may be best accomplished by identifying those at risk and modifying diet, weight, and exercise habits. Screening for prediabetes and diabetes is appropriate for men and women older than 45 years and all individuals with vascular disease. Insulin resistance and impaired insulin secretion is the major underlying defect in type 2 diabetes mellitus. It also affects 50% of nondiabetic subjects with a recent ischemic stroke. Emerging evidence has linked insulin resistance to the pathophysiologic derangements in type 2 diabetes mellitus that accelerate atherosclerosis. Treatment of insulin resistance with weight loss, exercise, or medication can correct these derangements, and represents a promising approach to stroke prevention.

Int J Obes Relat Metab Disord. 2004 Nov;28(11):1357-64.
Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1.
Skurk T, Hauner H.
1Else Kroner-Fresenius-Centre for Nutritional Medicine, Technical University of Munich, Freising-Weihenstephan, Germany.
Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinolysis in addition to hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes mellitus. Plasminogen activator inhibitor-1 (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator, and is a main determinant of fibrinolytic activity. There is now compelling evidence that obesity and, in particular, an abdominal type of body fat distribution are associated with elevated PAI-1 antigen and activity levels. Recent studies established that PAI-1 is expressed in adipose tissue. The greater the fat cell size and the adipose tissue mass, the greater is the contribution of adipose production to circulating PAI-1. Experimental data show that visceral adipose tissue has a higher capacity to produce PAI-1 than subcutaneous adipose tissue. Studies in human adipocytes indicate that PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, some fatty acids and, most potently, by cytokines such as tumour necrosis factor-alpha and transforming growth factor-beta, whereas catecholamines reduce PAI-1 production. Interestingly, pharmacological agents such as thiazolidinediones, metformin and AT(1)-receptor antagonists were found to reduce adipose expression of PAI-1. In addition, weight loss by dietary restriction or comprehensive lifestyle modification is effective in lowering PAI-1 plasma levels. In conclusion, impaired fibrinolysis in obesity is probably also due to an increased expression of PAI-1 in adipose tissue. An altered function of the endocrine system and an impaired auto-/paracrine function at the fat cell levels may mediate this disturbance of the fibrinolytic system and thereby increase the risk for cardiovascular disease.International Journal of Obesity (2004) 28, 1357-1364. doi:10.1038/sj.ijo.0802778 Published online 31 August 2004.

Prostaglandins Leukot Essent Fatty Acids. 2004 Nov;71(5):303-8.
Obese type 2 diabetics and obese patients have comparable plasma phospholipid fatty acid compositions deviating from that of healthy individuals.
Rodriguez Y, Giri M, Rottiers R, Christophe AB.
Department of Endocrinology and Metabolic Diseases, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. yanikrod@yahoo.com
There exist controversial reports regarding the differences in phospholipid fatty acids in type 2 diabetic and obese patients as compared to controls. The study was aimed at assessing the combined effect of type 2 diabetes and obesity on the fatty acid composition of plasma phospholipids. The experimental group consisted of 23 Belgian obese type 2 diabetics on Metformin. Two control groups were used: healthy lean and obese individuals in the same BMI range as the diabetics. Plasma phospholipids were isolated and their fatty acids and vinyl ether moieties were determined. Significance was set at P < 0.01. Plasma phospholipid fatty acids and plasmalogen-derived dimethyl acetals in diabetics deviated in many respects from these of lean controls but were not significantly different from those of obese non-diabetic patients. Therefore, the deviations of the fatty acid pattern of plasma phospholipids in type 2 diabetes may be attributed to obesity rather than to diabetes itself.

J Biol Chem. 2004 Oct 15;279(42):43940-51. Epub 2004 Jul 19.
Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo: ROLE OF MITOCHONDRIAL REACTIVE NITROGEN SPECIES.
Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG 4th, Schlattner U, Neumann D, Brownlee M, Freeman MB, Goldman MH.
Vascular Research Laboratory, Department of Surgery, Graduate School of Medicine, University of Tennessee, Knoxville, Tennessee 37920.
Metformin, one of the most commonly used drugs for the treatment of type II diabetes, was recently found to exert its therapeutic effects, at least in part, by activating the AMP-activated protein kinase (AMPK). However, the site of its action, as well as the mechanism to activate AMPK, remains elusive. Here we report how metformin activates AMPK. In cultured bovine aortic endothelial cells, metformin dose-dependently activated AMPK in parallel with increased detection of reactive nitrogen species (RNS). Further, either depletion of mitochondria or adenoviral overexpression of superoxide dismutases, as well as inhibition of nitric-oxide synthase, abolished the metformin-enhanced phosphorylations and activities of AMPK, implicating that activation of AMPK by metformin might be mediated by the mitochondria-derived RNS. Furthermore, administration of metformin, which increased 3-nitrotyrosine staining in hearts of C57BL6, resulted in parallel activation of AMPK in the aorta and hearts of C57BL6 mice but not in those of endothelial nitric-oxide synthase (eNOS) knockout mice in which metformin had no effect on 3-nitrotyrosine staining. Because the eNOS knockout mice expressed normal levels of AMPK-alpha that was activated by 5-aminoimidazole-4-carboxamide riboside, an AMPK agonist, these data indicate that RNS generated by metformin is required for AMPK activation in vivo. In addition, metformin significantly increased the co-immunoprecipitation of AMPK and its upstream kinase, LKB1, in C57BL6 mice administered to metformin in vivo. Using pharmacological and genetic inhibitors, we found that inhibition of either c-Src or PI3K abolished AMPK that was enhanced by metformin. We conclude that activation of AMPK by metformin might be mediated by mitochondria-derived RNS, and activation of the c-Src/PI3K pathway might generate a metabolite or other molecule inside the cell to promote AMPK activation by the LKB1 complex.

Best Pract Res Clin Obstet Gynaecol. 2004 Oct;18(5):773-88.
Management of infertility and prevention of ovarian hyperstimulation in women with polycystic ovary syndrome.
Homburg R.
Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Vrije Universiteit Medisch Centrum, De Boelelaan 1117, P O Box 7057, 1007 MB Amsterdam, The Netherlands; The Sackler Medical School, Tel Aviv University, Tel Aviv, Israel.
Anovulatory infertility is a prevalent presenting feature of polycystic ovary syndrome (PCOS). Restoration of ovulation might be achieved by ovarian stimulation or by reducing insulin and LH concentrations. Clomiphene citrate is the first-line ovulation-inducing agent, usually followed by direct stimulation with follicle stimulating hormone (FSH), if unsuccessful. The prevalent complications of ovarian hyperstimulation syndrome and multiple pregnancies can largely be avoided by administering FSH in a low dose and individualized regimen. Hyperinsulinaemia can be corrected by weight loss or insulin-sensitizing agents, such as metformin, which alone or in combination with other agents are capable of restoring ovulation. Advice about weight loss is critical in modern management of PCOS and infertility. Laparoscopic ovarian drilling produces similar results to FSH stimulation, and in vitro fertilization/embryo transfer (IVF/ET)-if all else fails-produces excellent results. The possible use of aromatase inhibitors, novel insulin sensitizers and in vitro maturation of oocytes is still being evaluated. The plethora of treatment options available today ensures that the great majority of women who are subfertile due to PCOS can be treated successfully.

Curr Med Res Opin. 2004 Oct;20(10):1633-40.
Healthcare costs and prescription adherence with introduction of thiazolidinedione therapy in Medicaid type 2 diabetic patients: a retrospective data analysis.
Balkrishnan R, Rajagopalan R, Shenolikar RA, Camacho FT, Whitmire JT, Anderson RT.
Division of Management and Policy Sciences, University of Texas School of Public Health, Houston, TX, USA. OBJECTIVES: Outcomes in patients with type 2 diabetes may vary depending on the antidiabetic medication used. Observational studies of outcomes of diabetes pharmacotherapy are needed to understand the implications of choice of controller in different populations. This study compared differences in total health care costs, medication adherence, and persistence in patients with type 2 diabetes enrolled in the North Carolina Medicaid Program that were newly started on thiazolidinedione (TZD) therapy with patients starting other oral antidiabetics during the same period. In addition differences among the TZDs with respect to these outcomes were examined. METHODS: A total of 1774 patients newly starting TZD therapy between July 2001 and June 2002 were compared to 1709 patients starting other oral antidiabetic medication (metformin or sulfonylureas) for health care costs and outcomes in the post-medication start year. In addition, a sub-group analysis of health care costs in patients starting either TZD (pioglitazone [n = 1086] versus rosiglitazone [N = 688]) was compared. All included patients had complete enrollment for the 24 months of follow-up. Multivariate techniques incorporating health care utilization in the year prior to start of new therapy were utilized to determine the cost impact of one therapy versus another. RESULTS: Results of multiple regression analyses suggest that patients starting TZD have better treatment adherence and persistence in the post-medication start year compared to patients starting other oral antidiabetics (13% increase in Medication Possession Ratios, and 10% increase in therapy persistence index, both p < 0.001). In addition, patients starting TZDs had 16.1% lower total annual health care costs (p < 0.01) compared to patients starting other oral antidiabetics. There were no differences in adherence and cost outcomes between the 2 TZDs. CONCLUSIONS: Introduction of thiazolidinedione therapy in a Medicaid-enrolled type 2 diabetic population was associated with significantly improved treatment adherence, persistence, and lower annual health care costs in the post-start year compared to patients starting other oral antidiabetics.

Diabet Med. 2004 Oct;21(10):1082-9.
The combination oral and nutritional treatment of late-onset diabetes mellitus (CONTROL DM) trial results.
Reboussin DM, Goff DC Jr, Lipkin EW, Herrington DM, Summerson J, Steffes M, Crouse RJ 3rd, Jovanovic L, Feinglos MN, Probstfield JL, Banerji MA, Pettitt DJ, Williamson J.
Department of Public Health Sciences,Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Abstract Objective To examine the effect of short-term improvements in glycaemic control on brachial artery endothelial function as a marker of cardiovascular health. Methods Persons with Type 2 diabetes who were poorly controlled on oral therapy were randomly assigned to monotherapy with repaglinide or combination therapy with repaglinide plus metformin. Brachial artery flow-mediated vasodilation was assessed by ultrasonography at randomization and following 16 weeks of therapy. The primary outcome was change in brachial artery endothelial function from baseline. Comparison of randomized groups was a secondary aim. Results Eighty-six participants were randomized, and 83 were followed to study completion. Post occlusion brachial artery vasodilation was 3.74% at baseline and 3.82% following 16 weeks of therapy (P = 0.77). The treatment effect was 0.08% (95% CI: -0.48%, 0.64%). No difference was seen between treatment groups (P = 0.69). Overall, A1C was reduced from 8.3% to 7.0%, with a greater reduction in the combination therapy group (from 8.4% to 6.7%) than in the monotherapy group (from 8.3% to 7.3%, p for difference between groups = 0.01). Statistically significant reductions were observed in fasting glucose, and plasminogen activator inhibitor-1. Statistically significant increases were observed for fasting insulin, uric acid, weight and BMI. Conclusions Brachial artery endothelial function was not influenced by short-term improvements in glycaemic control. The CONTROL DM group was successful in lowering A1C. Future research should explore more intensive and longer-lasting improvements in glycaemic control on endothelial function. Some data previously published in abstract form (Diabetes 2001; 50 (Suppl. 2): A217). Diabet. Med. (2004)

Expert Opin Ther Targets. 2004 Oct;8(5):401-8.
Role of oxidative stress and inflammation in the origin of Type 2 diabetes - a paradigm shift.
Pillarisetti S, Saxena U.
Reddy US Therapeutics, Dr Reddy Laboratories, 3065 Northwoods Circle, Norcross, GA 30071, USA. ram@reddyus.com.
In Type 2 diabetes the body either produces too little insulin, or does not respond well to it. Current pharmacological treatments, which are less than optimal, either target defective insulin secretion (sulfonylureas, glinides) or insulin resistance (metformin, thiazolidinediones). Exciting new research is now helping us to understand novel pathways that may contribute to defective insulin secretion as well as decreased response to insulin. Such pathways may explain the development of diabetes and associated complications (atherosclerosis and diabetic nephropathy). Understanding the way a cell metabolises glucose may be the key to understanding how cells secrete insulin and respond to it.

Fertil Steril. 2004 Oct;82(4):893-902.
Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity.
Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler JE.
Department of Medicine, Universite de Sherbrooke, Sherbrooke, Quebec, Canada.
OBJECTIVE: To determine whether insulin-sensitizing drugs would improve ovulation and T levels in women with polycystic ovary syndrome (PCOS), without clinical or biochemical criteria indicating insulin resistance and whether the combination of two distinct insulin-sensitizing drugs would be of any benefit over either drug alone. DESIGN: Randomized controlled double-blind trial. SETTING: A referral center in Caracas, Venezuela. PATIENT(S): One hundred twenty-eight nonobese PCOS women with normal indices of insulin sensitivity-that is, normal glucose tolerance, fasting insulin, peak insulin during an oral glucose tolerance test (OGTT), and fasting glucose-to-insulin ratio. Twenty-eight women were lost to follow-up initially and did not receive any intervention. INTERVENTION(S): One hundred women received twice daily one of the following for 6 months: metformin (850 mg), rosiglitazone (4 mg), combination of both drugs, or at least one placebo. MAIN OUTCOME MEASURE(S): Frequencies of ovulation and serum free T after 6 months. RESULT(S): Frequencies of ovulation were higher after treatment with an insulin-sensitizing drug (ovulations per subject in 6 months: metformin, 3.3; rosiglitazone, 2.4; and combination, 3.4) than with placebo (0.4). Ovulatory frequencies increased significantly more with metformin than rosiglitazone, and the combination was not more potent. After treatment, serum free-T levels were comparable among all active treatment groups (metformin: 2.34 pg/mL, rosiglitazone: 3.06 pg/mL, and combination: 2.39 pg/mL) and were significantly lower than in the placebo group (7.26 pg/mL). Compared with placebo, fasting insulin levels, area under the insulin curve during OGTT, the homeostatic model assessment of insulin sensitivity, and OGTT-derived insulin sensitivity index improved significantly after metformin or combination therapies but not after rosiglitazone. CONCLUSION(S): These findings suggest that insulin-sensitizing drugs increase ovulatory frequency and ameliorate hyperandrogenemia, even in nonobese women with PCOS who appear to have normal insulin sensitivity.

J Clin Endocrinol Metab. 2004 Oct;89(10):5043-7.
Increased Plasma Concentration of Macrophage Migration Inhibitory Factor (MIF) and MIF mRNA in Mononuclear Cells in the Obese and the Suppressive Action of Metformin.
Dandona P, Aljada A, Ghanim H, Mohanty P, Tripathy C, Hofmeyer D, Chaudhuri A.
D.Phil.(Oxon), F.A.C.P., F.A.C.C.,Diabetes-Endocrinology Center of Western New York, Chief of Endocrinology, State University of New York at Buffalo, 3 Gates Circle, Buffalo, New York 14209. pdandona@kaleidahealth.org.
The objective of the study was to determine whether plasma migration inhibitor factor (MIF) concentration and mononuclear cell (MNC) mRNA are elevated in obesity and whether treatment with metformin reduces plasma MIF concentration.Forty obese subjects [body mass index (BMI), 37.5 +/- 4.9 kg/m(2)] and 40 nonobese healthy subjects (BMI, 22.6 +/- 3.4 kg/m(2)) had their plasma MIF, glucose, insulin, free fatty acids (FFAs) and C-reactive protein (CRP) concentrations measured. Sixteen obese patients and 16 nonobese healthy subjects had RNA prepared from MNCs. Eight obese subjects with normal glucose concentration were treated with metformin 1 g (Glucophage XR; 1000 mg twice daily) twice daily for 6 wk. Eight obese subjects were used as controls. Plasma concentration of glucose, insulin, FFAs, and MIF was measured by appropriate assays. mRNA for MIF was measured by real-time PCR.Forty obese subjects had a fasting concentration of MIF of 2.8 +/- 2.0 ng/ml, whereas 40 nonobese subjects had a fasting MIF concentration of 1.2 +/- 0.6 ng/ml (P < 0.001). Plasma MIF concentrations were significantly related to BMI (r = 0.52; P < 0.001). mRNA for MIF was correlated to plasma FFAs (r = 0.40; P < 0.05) and plasma CRP (r = 0.42; P < 0.05) concentrations. Eight obese subjects had their fasting blood samples taken before and after taking a slow-release preparation of metformin at 1, 2, 4, and 6 wk. The mean plasma concentration fell from 2.3 +/- 1.4 to 1.6 +/- 1.2 ng/ml at 6 wk (P < 0.05). Obese subjects not on treatment with metformin showed no change. During the period of treatment with metformin, the body weight did not change and the plasma concentration of glucose, insulin, and FFAs did not alter.We conclude that: 1) plasma MIF concentrations and MIF mRNA expression in the MNCs are elevated in the obese, consistent with a proinflammatory state in obesity; 2) these increases in MIF are related to BMI, FFA concentrations, and CRP; 3) metformin suppresses plasma MIF concentrations in the obese, suggestive of an antiinflammatory effect of this drug; and 4) this action of metformin may contribute to a potential antiatherogenic effect, which may have implications for the reduced cardiovascular mortality observed with metformin therapy in type 2 diabetes mellitus.

J Clin Endocrinol Metab. 2004 Oct;89(10):4801-9.
Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: a prospective parallel randomized double-blind placebo-controlled trial.
Palomba S, Orio F Jr, Nardo LG, Falbo A, Russo T, Corea D, Doldo P, Lombardi G, Tolino A, Colao A, Zullo F.
Department of Gynecology and Obstetrics, University "Magna Graecia" of Catanzaro, Via Nicolardi 188, 80131 Naples, Italy. stefanopalomba@tin.it.
At present, it is unclear what the role is of laparoscopic ovarian diathermy (LOD) and of metformin administration as second-line treatments for ovulation induction in women with polycystic ovary syndrome (PCOS) after failure of clomiphene citrate (CC) treatment. The aim of the present study was to compare in a randomized double-blind placebo-controlled fashion the effectiveness of LOD with metformin administration in the treatment of CC-resistant women with PCOS. A total of 120 overweight primary infertile anovulatory CC-resistant women with PCOS were enrolled and randomized into two groups of treatment. Group A underwent diagnostic laparoscopy, whereas group B underwent LOD. At hospital discharge, the patients were treated for 6 months with metformin cloridrate (group A; 850 mg twice daily) or with multivitamins (group B). The ovulation, pregnancy, abortion, and live-birth rates were evaluated. At the end of the study, the total ovulation rate was not statistically different between both treatment groups (54.8 vs. 55.1% in groups A and B, respectively), whereas the pregnancy (18.6 vs. 13.4%), the abortion (15.4 vs. 29.0%), and the live-birth (82.1 vs. 64.5%) rates were significantly (P < 0.05) different between the two groups. Our data show that metformin administration is more effective than LOD in overall reproductive outcomes in overweight infertile CC-resistant women with PCOS.

J Clin Endocrinol Metab. 2004 Oct;89(10):4797-800.
Metformin--comparison with other therapies in ovulation induction in polycystic ovary syndrome.
Norman RJ.
Research Centre for Reproductive Health and Repromed, Department of Obstetrics and Gynaecology, University of Adelaide, The Queen Elizabeth Hospital, Woodville SA 5011, Australia. robert.norman@adelaide.edu.au.

J Clin Pharm Ther. 2004 Oct;29(5):449-54.
Do risk factors for lactic acidosis influence dosing of metformin?
Millican S, Cottrell N, Green B.
School of Pharmacy, University of Queensland, Brisbane, Australia.
Summary Background: Metformin is commonly prescribed to treat type 2 diabetes mellitus, however it is associated with the potentially lethal condition of lactic acidosis. Prescribing guidelines have been developed to minimize the risk of lactic acidosis development, although some suggest they are inappropriate and have created confusion amongst prescribers. The aim of this study was to investigate whether metformin dose was influenced by the presence of risk factors for lactic acidosis. Methods: The study was prospective, and retrieved information from patients admitted to hospital who were prescribed metformin at their time of admission. Results: Eighty-three patients were included in the study, 60 of whom had a least one risk factor for lactic acidosis. Of those 60 patients, 78.3% had a dose adjustment, with renal impairment, hepatic impairment, surgery and use of radiological contrast media - the risk factors most likely to result in a dose adjustment. When dose adjustments did occur, metformin was withheld on 88.7% of occasions. Conclusion: Metformin dose was influenced by the presence of risk factors for lactic acidosis, although it was dependent upon the number and particular risk factor/s present.

J Fam Pract. 2004 Oct;53(10):815-22.
Optimizing combination therapy for type 2 diabetes n adolescents and adults: A case-based approach.
Elasy TA, Levy P, Davis SN.
Division of General Internal Medicine, Vanderbilt University Medical Center, Nashville, TN USA.
Children and adolescents who are overweight and have additional risk factors (ie, high-risk ethnic group or signs of insulin resistance) should be screened for diabetes every 2 years (strength of recommendation [SOR]: C). Management of type 2 diabetes in all age groups requires a multifactorial approach that addresses not only glycemic control (A1C <7%) but also other cardiovascular risk factors such as hypertension, dyslipidemia, and obesity (SOR: A). Most patients with type 2 diabetes will eventually require combination therapy with 2 or more agents to attain and maintain glycemic control (SOR: A). Combining an insulin secretagogue (ie, sulfonylurea or meglitinide) and an insulin sensitizer (ie, metformin or a glitazone) capitalizes on unique mechanisms of action and results in significant A1C lowering (SOR: C). If a patient is unable to achieve glycemic control on 2 oral agents, insulin therapy is an appropriate consideration and should be added to oral agents (rather than substituted) (SOR: B).

J Hand Surg [Br]. 2004 Oct;29(5):423-6.
Dupuytren's disease risk factors.
Geoghegan JM, Forbes J, Clark DI, Smith C, Hubbard R.
Department of Trauma and Orthopaedics, Derbyshire Royal Infirmary, UK. john.geoghegan@ntlworld.com
Dupuytren's is a common problem, but little is known about its aetiology. We have undertaken a large case-control study to assess and quantify the relative contributions of diabetes and epilepsy as risk factors for Dupuytren's in the community. Cases were patients with a diagnosis of Dupuytren's disease and, for each, two controls were individually matched by age, sex, and general practice. Our dataset included 821 cases and 1,642 controls. Five hundred and eighty-eight (72%) of the cases were men. The mean age at diagnosis was 62 (range 24-97) years. Diabetes was a significant risk factor for Dupuytren's disease (OR=1.75) and there was an increased risk for medicinally treated diabetes (metformin--OR=3.56; sulphonylureas--OR=1.75) and particularly insulin controlled (OR=4.38) rather than diet-controlled diabetes. Epilepsy (OR=1.12) and anti-epileptic medications were not associated with Dupuytren's disease. Ascertainment bias in previous studies may explain the reported association with epilepsy.

Biochem J. 2004 Sep 15;382(Pt 3):877-84.
Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study.
Guigas B, Detaille D, Chauvin C, Batandier C, De Oliveira F, Fontaine E, Leverve X.
INSERM E-0221 Bioenergetique Fondamentale et Appliquee, Universite Joseph Fourier, BP 53X, 38041 Grenoble Cedex, Grenoble, France.
Metformin, a drug widely used in the treatment of Type II diabetes, has recently received attention owing to new findings regarding its mitochondrial and cellular effects. In the present study, the effects of metformin on respiration, complex 1 activity, mitochondrial permeability transition, cytochrome c release and cell death were investigated in cultured cells from a human carcinoma-derived cell line (KB cells). Metformin significantly decreased respiration both in intact cells and after permeabilization. This was due to a mild and specific inhibition of the respiratory chain complex 1. In addition, metformin prevented to a significant extent mitochondrial permeability transition both in permeabilized cells, as induced by calcium, and in intact cells, as induced by the glutathione-oxidizing agent t-butyl hydroperoxide. This effect was equivalent to that of cyclosporin A, the reference inhibitor. Finally, metformin impaired the t-butyl hydroperoxide-induced cell death, as judged by Trypan Blue exclusion, propidium iodide staining and cytochrome c release. We propose that metformin prevents the permeability transition-related commitment to cell death in relation to its mild inhibitory effect on complex 1, which is responsible for a decreased probability of mitochondrial permeability transition.

J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Sep 5;808(2):215-9.
Rapid and sensitive liquid chromatography-tandem mass spectrometric method for the quantitation of metformin in human plasma.
Wang Y, Tang Y, Gu J, Fawcett JP, Bai X.
Research Center for Drug Metabolism, Jilin University, Changchun 130023, China.
A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS-MS) method for the determination of metformin in human plasma using phenformin as internal standard has been developed and validated. Sample preparation of plasma involved acidification with acetic acid, deproteination with acetonitrile and washing with dichloromethane. Samples were then analyzed by HPLC on a short Nucleosil C18 column (5 microm, 50 mm x 4.6 mm i.d.) using a mobile phase consisting of acetonitrile:methanol:10mM ammonium acetate pH 7.0 (20:20:60, v/v/v) delivered at 0.65 ml/min. Detection was performed using an Applied Biosystems Sciex API 4000 mass spectrometer set at unit resolution in the multiple reaction monitoring (MRM) mode. Atmospheric pressure chemical ionization (APCI) was used for ion production. The assay was linear over the range 1-2000 ng/ml with intra- and inter-day precision of <8.6% and accuracy in the range 91-110%. The limit of detection was 250 pg/ml in plasma. The method was successfully applied to a clinical pharmacokinetic study of an extended-release tablet of metformin hydrochloride (500 mg) administered as a single oral dose.

Biopharm Drug Dispos. 2004 Sep;25(6):261-3.
Pharmacokinetics and dose proportionality of extended-release metformin following administration of 1000, 1500, 2000 and 2500 mg in healthy volunteers.
Cullen E, Liao J, Lukacsko P, Niecestro R, Friedhoff L.
Andrx Laboratories, Hackensack, NJ 07601, USA. eic@pspg.com
The pharmacokinetics and dose-exposure relationship of an extended-release formulation of metformin (ER-metformin) was investigated in a randomized, single-dose, four-period crossover study in 24 healthy male volunteers. During each study period, subjects received a randomly assigned dose containing 1000, 1500, 2000 or 2500 mg metformin. Blood samples were drawn 0-72 h after dosing for pharmacokinetic and dose-proportionality assessment. Although several pairwise comparisons between dose groups were significant (p<0.05) with respect to dose-normalized C(max), AUC(0-72 h), and AUC( infinity ), the magnitude of the difference across the dose range was <20% for AUC(0-72 h) and AUC( infinity ), and was < or = 30% for C(max). The results indicate a consistent and predictable increase in metformin exposure with an extended-release formulation of metformin over 1000 to 2500 mg.

BMJ. 2003 Oct 25;327(7421):951-3.
Metformin in polycystic ovary syndrome: systematic review and meta-analysis.
Lord JM, Flight IH, Norman RJ.
Department of Endocrinology and Metabolism, Peninsula Medical School, South West Centre for Reproductive Medicine, Derriford Hospital, Plymouth, Devon, PL6 8DH.
OBJECTIVE: To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent. SELECTION OF STUDIES: 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence. MAIN OUTCOME MEASURE: Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome. RESULTS: Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect on body mass index or waist:hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance. CONCLUSIONS: Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.

Diabetes Care. 2004 Jan;27(1):41-6.
Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes.
Lawrence JM, Reid J, Taylor GJ, Stirling C, Reckless JP.
Diabetes and Lipid Research Group, Wolfson Centre, Royal United Hospital, Bath, U.K. Senior Statistician, Department of Medical Sciences, University of Bath, Bath, U.K.
OBJECTIVE:-To compare effects of different oral hypoglycemic drugs as first-line therapy on lipoprotein subfractions in type 2 diabetes. RESEARCH DESIGN AND METHODS-Sixty overweight type 2 diabetic patients not on lipid-lowering therapy were randomized to metformin, pioglitazone, or gliclazide after a 3-month dietary run-in. Drug doses were uptitrated for 3 months to optimize glycemia and were kept fixed for a further 3 months. LDL subfractions (LDL(1), LDL(2), and LDL(3)) were prepared by density gradient ultracentrifugation at randomization and study end. Triglycerides, cholesterol, total protein, and phospholipids were measured and mass of subfractions calculated. HDL subfractions were prepared by precipitation. The primary end point was change in proportion of LDL as LDL(3). RESULTS:-HbA(1c), triglycerides, glucose, and cholesterol were comparable across groups at baseline and over time. LDL(3) mass and the LDL(3)-to-LDL ratio fell with pioglitazone (LDL(3) mass 36.2 to 28.0 mg/dl, P < 0.01; LDL(3)-to-LDL 19.2:13.3%, P < 0.01) and metformin (42.7 to 31.5 mg/dl, P < 0.01; 21.3:16.2%, P < 0.01, respectively) with no change on gliclazide. LDL(3) reductions were associated with reciprocal LDL(1) increases. Changes were independent of BMI, glycemic control, and triglycerides. Total HDL cholesterol increased on pioglitazone (1.28 to 1.36 mmol/l, P = 0.02) but not gliclazide (1.39 to 1.37 mmol/l, P = NS) or metformin (1.26 to 1.18 mmol/l, P = NS), largely due to an HDL(2) increase (0.3 to 0.4 mmol/l, P < 0.05). HDL(3) cholesterol fell on metformin (0.9 to 0.85 mmol/l, P < 0.01). On pioglitazone and metformin, the HDL(2)-to-HDL(3) ratio increased compared with no change on gliclazide. CONCLUSIONS:-For the same improvement in glycemic control, pioglitazone and metformin produce favorable changes in HDL and LDL subfractions compared with gliclazide in overweight type 2 diabetic patients. Such changes may be associated with reduced atherosclerosis risk and may inform the choice of initial oral hypoglycemic agent.

J Chin Med Assoc. 2003 Aug;66(8):505-8.
Chu CK, Chang YT, Lee BJ, Hu SY, Hu WH, Yang DY.
Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.
Metformin-associated lactic acidosis and acute renal failure in a type 2 diabetic patient.
Metformin belongs to a class of drugs known as the biguanides that are widely used in the treatment of type 2 diabetes mellitus. Its association with lactic acidosis is well established, although rare. Metformin-associated lactic acidosis is recognized as a potentially lethal condition that can occur in patients with contraindications to the drug, such as renal dysfunction, liver diseases, alcoholism, and cardiopulmonary diseases. In these cases, the plasma concentration of metformin is not necessarily abnormally high. We describe a 75-year-old diabetic woman with acute renal failure and life-threatening lactic acidosis due to metformin intoxication. Clinical manifestations included vomiting, diarrhea, hypothermia, hypotension and transitory blindness. Her initial renal function was recovered after hemodialysis and she was discharged 3 months after admission.