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PubMed2006

Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats: involvement of CYP2C11, 2D1 and 3A1/2 for the metabolism of metformin.

BACKGROUND AND PURPOSE: The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore, a series of experiments using various inducers and inhibitors of CYP isozymes was conducted to find out what types of CYP isozymes are involved in the metabolism of metformin in rats. EXPERIMENTAL APPROACH: Metformin at a dose of 100 mg kg(-1) was administered intravenously to rats. The rats were pretreated with CYP inducers such as 3-methylcholanthrene, orphenadrine, isoniazid, and dexamethasone (major inducers of CYP1A1/2, 2B1/2, 2E1, and 3A1/2, respectively, in rats), or CYP inhibitors such as SKF-525 (a non-specific inhibitor of CYP isozymes), and sulfaphenazole, quinine, and troleandomycin (major inhibitors of CYP2C11, 2D1, and 3A1/2, respectively, in rats). The time-averaged non-renal clearance (CLNR) of metformin was compared with that of controls. KEY RESULTS: In rats pretreated with dexamethasone, the CLNR was significantly faster (57% increase) than for the controls. In rats pretreated with SKF-525-A, sulfaphenazole, quinine, and troleandomycin, the CLNR was significantly slower (24.3, 62.9, 77.6, and 78.7% decrease, respectively) than for the controls. However, the CLNR values did not significantly different in the rats pretreated with 3-methylencholanthrene, orphenadrine, and isoniazid compared with the controls. CONCLUSIONS AND IMPLICATIONS: Our data suggest that metformin was metabolized mainly via CYP2C11, 2D1, and 3A1/2 in rats. This result could contribute to understanding of the possible changes in metformin pharmacokinetics in disease models where CYP2C11 and/or 3A1/2 are altered.

Alcohol Oxidoreductases↗
PubMed2000

Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells.

Because metformin affects glucose and free fatty acid (FFA) metabolism in peripheral insulin target tissues, we investigated the effect of this drug in restoring a normal secretory pattern in rat pancreatic islets whose function has been impaired by chronic exposure to elevated FFA or glucose concentrations. We cultured rat pancreatic islets with or without FFA (2 mmol/l oleate/palmitate 2:1) or high glucose (16.7 mmol/l) concentrations in the presence or absence of metformin (0.25-12.5 microg/ml) and then measured insulin release, glucose utilization, glucose, and FFA oxidation. When compared with control islets, islets exposed to high FFA or glucose concentrations showed an increased basal and a decreased glucose-induced insulin release. In islets cultured for an additional 24 h with FFA or glucose in the presence of metformin (2.5 microg/ml), both basal and glucose-induced insulin secretions were restored. Both glucose utilization and glucose oxidation were altered in islets pre-exposed to high FFA or glucose concentrations. In particular, regarding control islets, glucose utilization was increased at 2.8 mmol/l glucose and decreased at 16.7 mmol/l glucose; glucose oxidation was similar to control islets at 2.8 mmol/l glucose but decreased at 16.7 mmol/l glucose. In contrast, oleate oxidation was increased in islets pre-exposed to FFA. All of these abnormalities were reversed in islets cultured for an additional 24 h with high FFA or glucose concentrations in the presence of metformin (2.5 microg/ml). In conclusion, our data show that metformin is able to restore the intracellular abnormalities of glucose and FFA metabolism and to restore a normal secretory pattern in rat pancreatic islets whose secretory function has been impaired by chronic exposure to elevated FFA or glucose levels. These data raise the possibility that, in diabetic patients, metformin (in addition to its peripheral effects) may have a direct beneficial effect on the beta-cell secretory function.

Animals↗
PubMed2003

Efficacy and safety of combination therapy: repaglinide plus metformin versus nateglinide plus metformin.

OBJECTIVE: An open-label, parallel-group, randomized, multicenter trial was conducted to compare efficacy and safety of repaglinide versus nateglinide, when used in a combination regimen with metformin for treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: Enrolled patients (n = 192) had HbA(1c) >7% and < or =12% during previous treatment with a sulfonylurea, metformin, or low-dose Glucovance (glyburide < or =2.5 mg, metformin < or =500 mg). After a 4-week metformin run-in therapy period (doses escalated to 1,000 mg b.i.d.), patients were randomized to addition of repaglinide (n = 96) (1 mg/meal, maximum 4 mg/meal) or nateglinide (n = 96) (120 mg/meal, reduced to 60 mg if needed) to the regimen for 16 weeks. Glucose, insulin, and glucagon were assessed after a liquid test meal at baseline and week 16. RESULTS: Final HbA(1c) values were lower for repaglinide/metformin treatment than for nateglinide/metformin (7.1 vs. 7.5%). Repaglinide/metformin therapy showed significantly greater mean reductions of HbA(1c) (-1.28 vs. -0.67%; P < 0.001) and of fasting plasma glucose (FPG) (-39 vs. -21 mg/dl; P = 0.002). Self-monitoring of blood glucose profiles were significantly lower for repaglinide/metformin before breakfast, before lunch, and at 2:00 A.M. Changes in the area under the curve of postprandial glucose, insulin, or glucagon peaks after a test meal were not significantly different for the two treatment groups during this study. Median final doses were 5.0 mg/day for repaglinide and 360 mg/day for nateglinide. Safety assessments were comparable for the two regimens. CONCLUSIONS: The addition of repaglinide to metformin therapy resulted in reductions of HbA(1c) and FPG values that were significantly greater than the reductions observed for addition of nateglinide.

Area Under Curve↗
PubMed2006

Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease.

BACKGROUND: Adding metformin to clomiphene citrate in clomiphene-resistant polycystic ovary syndrome (PCOS) patients increases ovulatory response. However, because of anti-estrogenic effects of clomiphene it may be associated with lower pregnancy rate, offsetting the ovulation rate benefit. Letrozole is an aromatase inhibitor which induces ovulation without anti-estrogenic effects. METHODS: Infertile women with PCOS were randomly divided into metformin-letrozole (29 patients) and metformin-clomiphene groups (30 patients). After an initial 6-8 weeks of metformin, they received either letrozole (2.5 mg) or clomiphene (100 mg) from day 3-7 of their menstrual cycle. Estradiol (E2) levels, number of follicles, pregnancy rates and endometrial thickness were measured on the day of HCG administration. RESULTS: Mean total E2 and E2 per mature follicle were significantly higher in clomiphene group without a difference in mean number of mature follicles >18 mm and ovulation rate. Endometrial thickness was significantly higher in letrozole group. The pregnancy rate in letrozole group (10 patients, 34.50%) as compared with clomiphene group (5 patients, 16.67%) did not show significant difference, whereas full-term pregnancies were higher in letrozole group [10 patients (34.50%) versus 3 patients (10%)]. CONCLUSION: In clomiphene-resistant PCOS patients, the combination of letrozole and metformin leads to higher full-term pregnancies.

Adult↗
PubMed2006

Comparison of nateglinide and gliclazide in combination with metformin, for treatment of patients with Type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone.

AIM: To compare the effects of nateglinide plus metformin with gliclazide plus metformin on glycaemic control in patients with Type 2 diabetes. METHODS: Double-blind, double-dummy, parallel group, randomized, multicentre study over 24 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to additionally receive nateglinide (n = 133) or gliclazide (n = 129). Changes from baseline in HbA1c, fasting plasma glucose (FPG) and mealtime glucose and insulin excursions were examined. RESULTS: HbA1c was significantly (P < 0.001) decreased from baseline in both treatment groups (mean changes: nateglinide -0.41%, gliclazide -0.57%), but with no significant difference between treatments. Proportions of patients achieving a reduction of HbA1c >or= 0.5% or an end point HbA1c < 7% were also similar (nateglinide 58.1%, gliclazide 60.2%). Changes from baseline in FPG were similarly significant in both treatment groups (nateglinide -0.63, gliclazide -0.82 mmol/l). Reduction from baseline in maximum postprandial glucose excursion were significant in the nateglinide group only (nateglinide -0.71, gliclazide -0.10 mmol/l; P = 0.037 for difference). Postprandial insulin levels were significantly higher with nateglinide compared with gliclazide. The overall rate of hypoglycaemia events was similar in the nateglinide group compared with the gliclazide group. CONCLUSIONS: No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. However, the nateglinide combination demonstrated better postprandial glucose control.

Adult↗
PubMed2005

Antithrombotic effects of rosiglitazone-metformin versus glimepiride-metformin combination therapy in patients with type 2 diabetes mellitus and metabolic syndrome.

STUDY OBJECTIVE: To evaluate the differential effect on coagulation and fibrinolysis parameters of combination therapy with glimepiride-metformin and with rosiglitazone-metformin beyond their effect on glucose metabolism in patients with type 2 diabetes and metabolic syndrome. DESIGN: Multicenter, double-blind, randomized, controlled trial. SETTING: Two university-affiliated medical centers in Italy. PATIENTS: Ninety-five patients with type 2 diabetes for at least 6 months without glycemic control by diet and oral hypoglycemic agents to their maximum tolerated dosage and who also had metabolic syndrome. INTERVENTION: All 95 patients received metformin 1500 mg/day. In a randomized manner, 47 patients received glimepiride 2 mg/day and 48 patients received rosiglitazone 4 mg/day. MEASUREMENTS AND MAIN RESULTS: Body mass index (BMI), glycemic control, and coagulation and fibrinolysis parameters were evaluated at 3, 6, 9, and 12 months of treatment. Compared with baseline values, significant decreases in BMI, fasting plasma glucose, postprandial plasma glucose, and hemoglobin A1c were observed at 12 months in both the glimepiride and rosiglitazone groups (p<0.05 and p<0.01, respectively). Decreases in fasting plasma insulin and postprandial plasma insulin were observed at 12 months (p<0.05 and p<0.01, respectively) compared with baseline values in the rosiglitazone group. Furthermore, improvement in the Homeostasis Model Assessment index was observed only at 9 and 12 months (p<0.05 and p<0.01, respectively) compared with baseline in the rosiglitazone group. Significant improvement in plasminogen activator inhibitor (PAI)-1 was present in the rosiglitazone group after 9 months (p<0.05), and significant PAI-1 improvement was observed in the glimepiride and rosiglitazone groups after 12 months (p<0.05 and p<0.01, respectively). CONCLUSIONS: The rosiglitazone-metformin combination significantly improved the long-term control of all insulin resistance-related parameters compared with the glimepiride-metformin combination. However, both combinations were associated with a slight but statistically significant improvement in PAI-1 value, related to a similar reduction in insulin resistance.

Blood Glucose↗
PubMed2004

Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy.

OBJECTIVE: This study aimed to assess glycemic response to a mixture of 75% insulin lispro protamine suspension and 25% insulin lispro (Mix 75/25) BID plus metformin versus insulin glargine QD plus metformin in patients with type 2 diabetes mellitus (DM). METHODS: Adults new to insulin therapy were enrolled in a multicenter, randomized, prospective, open-label, crossover study with 16 weeks on each treatment. Variables included glycosylated hemoglobin (HbA(1c)), hypoglycemia rate, fasting blood glucose (FBG), 2-hour postprandial blood glucose (ppBG), and rise in blood glucose after meals. RESULTS: One hundred five patients (mean age, 55 years) were randomized. There was no difference in baseline mean values for either treatment sequence group for body mass index, duration of DM, or HbA(1c). Ninety-five patients completed the study and 67 were included in the efficacy analysis. Mix 75/25 was associated with lower mean (SD) HbA(1c) at end point (7.4% [1.1%] vs 7.8% [1.1%]; P = 0.002). More patients using Mix 75/25 achieved target HbA(1c) < or =7.0% (42% [30/71] vs 18% [13/71]; P < 0.001). With Mix 75/25, the mean (SD) 2-hour ppBG was similar after lunch but lower after breakfast (156.4 [43.6] vs 171.1 [44.9] mg/dL; P = 0.012) and dinner (164.8 [42.5] mg/dL vs 193.8 [51.0] mg/dL; P < 0.001), although FBG was higher (139.3 [36.6] mg/dL vs 123.9 [34.9] mg/dL; P < 0.001). Rise in ppBG was lower with Mix 75/25 after breakfast (16.9 [47.0] mg/dL vs 47.4 [34.8] mg/dL; P < 0.001) and dinner (14.2 [44.1] mg/dL vs 45.9 [41.3] mg/dL; P < 0.001). Gain in mean (SD) body weight was greater with Mix 75/25 than insulin glargine (2.3 [4.0] kg vs 1.6 [4.0] kg; P = 0.006). For all randomized patients, mean (SD) hypoglycemia rates were lower with insulin glargine (0.68 [1.38] vs 0.39 [1.24] episodes/patient per 30 days; P = 0.041), although nocturnal hypoglycemia was similar. CONCLUSION: In this study population, Mix 75/25 plus metformin was associated with lower HbA(1c) than insulin glargine plus metformin, smaller rise in ppBG after breakfast and dinner, and higher proportion of patients achieving HbA(1c) < or =7.0%, with a slight increase in overall (but not nocturnal) hypoglycemia.

Adult↗
PubMed2003

[Metformin-associated lactic acidosis remains a serious complication of metformin therapy].

We report 4 cases of lactic acidosis in diabetic patients usually treated with metformin. For the first 3 patients, the clinical history was similar because lactic acidosis was precipitated by gastro-intestinal disorders whereas all of them were simultaneously treated with several nephrotoxic drugs. These 3 patients presented with acute renal failure on arrival at hospital. Their issue was fatal whereas any obvious cause of overproduction of lactate was found. The fourth case, which was due to a voluntary intoxication, was the only one presenting with a favourable evolution. The metformin plasma and red blood cell levels were performed for 2 of 4 patients and confirmed the overdose. These observations remind that metformin-associated lactic acidosis remains a serious complication, and that medical doctors must respect strictly contra-indications and guidelines for withdrawing metformin.

Acidosis, Lactic↗
PubMed2006

Mathematical modeling shows exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin or metformin and a sulfonylurea.

The incretin mimetic exenatide improved glycemic control and reduced body weight in patients with type 2 diabetes inadequately controlled with metformin+/-a sulfonylurea. We assessed postprandial beta-cell function by mathematical modeling, independent of confounding effects from differing ambient glucose levels among treatments. Subjects were 63% males, 55+/-10 years, BMI 33+/-6 kg/m2, HbA1C 8.1+/-1.1% (+/- SD) randomized to 5 microg exenatide or placebo twice daily for 4 weeks. Subsequently, one arm remained at 5 microg twice daily, one arm escalated to 10 microg twice daily, and one treatment arm remained on placebo for 26 weeks. Subjects continued metformin+/-a sulfonylurea. A subset with meal tests at baseline and week 30 were analyzed (n=73). Outcome measures were the model-based beta-cell function parameters dose-response relating insulin secretion to glucose concentration, rate sensitivity, and potentiation. Exenatide reduced postprandial glucose excursions. Modeling predicted an upward shift of the beta-cell dose-response. Model-predicted insulin secretion rate at a reference glucose concentration increased 72% (10 microg), increased 40% (5 microg), or decreased 21% (placebo) at week 30 [ p=0.015 (10 microg); p=0.045 (5 microg); vs. placebo]. At week 30, the 2-hour post-meal to basal potentiation factor ratio was increased to 1.53+/-0.10 (10 microg; p=0.0142 vs. placebo) or 1.40+/-0.08 (5 microg; p=0.0402 vs. placebo) compared with 1.15+/-0.06 (placebo). Exenatide caused an upward shift of the beta-cell dose-response and enhanced potentiation of insulin secretion. This model suggests exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin+/-a sulfonylurea.

Adult↗
PubMed2006

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.

OBJECTIVE: The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, added to ongoing metformin therapy, were assessed in patients with type 2 diabetes who had inadequate glycemic control (HbA(1c) [A1C] >or=7 and or=1,500 mg/day) were randomly assigned to receive the addition of placebo or sitagliptin 100 mg once-daily in a 1:2 ratio for 24 weeks. Patients exceeding specific glycemic limits were provided rescue therapy (pioglitazone) until the end of the study. The efficacy analyses were based on an all-patients-treated population using an ANCOVA and excluded data obtained after glycemic rescue. RESULTS: At week 24, sitagliptin treatment led to significant reductions compared with placebo in A1C (-0.65%), fasting plasma glucose, and 2-h postmeal glucose. Fasting insulin, fasting C-peptide, fasting proinsulin-to-insulin ratio, postmeal insulin and C-peptide areas under the curve (AUCs), postmeal insulin AUC-to-glucose AUC ratio, homeostasis model assessment of beta-cell function, and quantitative insulin sensitivity check index were significantly improved with sitagliptin relative to placebo. A significantly greater proportion of patients achieved an A1C <7% with sitagliptin (47.0%) than with placebo (18.3%). There was no increased risk of hypoglycemia or gastrointestinal adverse experiences with sitagliptin compared with placebo. Body weight decreased similarly with sitagliptin and placebo. CONCLUSIONS: Sitagliptin 100 mg once-daily added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone.

Adenosine Deaminase Inhibitors↗
PubMed2000

[Severe lactic acidosis due to metformin therapy in a patient with contra-indications for metformin].

A 52-year-old woman with a medical history of diabetes mellitus type 2, chronic alcoholism and liver function disorders was hospitalized because of complaints of haematemesis, abdominal complaints and dyspnoea. This was due to a severe lactic acidosis caused by acute alcohol intoxication and the use of metformin. With bicarbonate infusion and haemofiltration, the lactic acidosis disappeared, but she developed a distributive shock with multiple organ failure and died 23 days after admission. Lactic acidosis is a rare but serious adverse effect of metformin. Almost all patients described had contraindications to the drug, like renal failure, liver disease, alcohol abuse, and intercurrent conditions causing hypoxia or ischaemia. It is important to be aware of the circumstances in which metformin should not be prescribed.

Acidosis, Lactic↗
PubMed1997

Synthesis and antitumor activity of the metformin platinum (IV) complex. Crystal structure of the tetrachloro(metformin)platinum (IV) dimethylsulfoxide solvate.

The synthesis of (metformin) tetrachloroplatinum (IV) was investigated (metformin is N,N-dimethylbiguanide). It crystallizes with one dimethylsulfoxide molecule as solvate in the monoclinic system, space group P2(1)/n (No. 14) with Z = 4. The cell dimensions are: a = 13.136(7), b = 9.424(2), c = 14.009(8) A, beta = 111.96(4) degrees, V = 1608.4(2) A3. Of the 4269 independent nonzero reflections collected, 1979 with I > 3 sigma (I) were considered and used in the calculations. The structure was refined to R = 0.043 and wR = 0.045. The platinum coordination is octahedral, built up from four chloride anions and one bidentate chelating ligand via the two imine nitrogen atoms cis position. The distances and angles are typical of six-membered rings that have similar donor atoms. The complex was evaluated in vitro and in vivo on murine P388 leukemia. It was found to be as potent as cis-dichlorodiammine platinum (II), CDDP, in inhibiting the proliferation of the sensitive P388 cells. However the resistant P388/CDDP cells were threefold more sensitive to the compound than to CDDP. The two compounds induced a similar perturbation in the G2+M phases of the cell-cycle. The complex was less active than CDDP in vivo on P388 leukemia when administered i.p. (intra peritoneal) on day 1.

Animals↗
PubMed2006

Effect of metformin plus roziglitazone compared with metformin alone on glycaemic control in well-controlled Type 2 diabetes.

AIMS: To investigate the effect of metformin plus roziglitazione (RSGMET) compared with metformin alone (MET) on glycaemic control in well-controlled Type 2 diabetes. METHODS: Subjects (drug naïve or those on glucose-lowering monotherapy) were randomized (n = 526), following a 4-week placebo run-in period, to RSGMET [4 mg rosiglitazone (RSG)/500 mg MET] or MET 500 mg. From weeks 2-18, medication was escalated every 4 weeks (based on gastrointestinal tolerability), then remained at RSGMET 8 mg/2 g or MET 3 g for 14 weeks. RESULTS: RSGMET reduced HbA(1c) from 7.2 +/- 0.6 to 6.7 +/- 0.8% at week 32, compared with a reduction from 7.2 +/- 0.6 to 6.8 +/- 0.9% with MET (treatment difference -0.13%; P = 0.0357). More subjects achieved an HbA(1c) value of </= 6.5% at week 32 with RSGMET (51.6 vs. 43.7%), but the treatment difference was not significant (odds ratio 1.37, P = 0.0949). RSGMET produced larger reductions from baseline in mean fasting plasma glucose (adjusted difference -0.62 mmol/l, P < 0.0001), with the odds ratio of achieving a target of < 7.0 mmol/l being 2.33 (P < 0.0001). Statistically significant differences in favour of RSGMET relative to MET were seen for homeostatic model assessment (HOMA)-derived estimates of insulin sensitivity and pancreatic B-cell function, C-reactive protein (CRP), and systolic blood pressure. Overall rates of gastrointestinal adverse events (relevant to the known profile of MET) were comparable, but with a lower incidence of diarrhoea (8 vs. 18%) with RSGMET. Hypoglycaemia was reported in </= 7% subjects per group. CONCLUSIONS: RSGMET provided similar short-term glycaemic control to MET with greater improvements in estimates of insulin sensitivity, B-cell function and CRP, with less diarrhoea and low risk of biochemical hypoglycaemia, suggesting that early use of combination therapy may be appropriate.

Blood Glucose↗
PubMed2004

Comparing the long-term cost-effectiveness of repaglinide plus metformin versus nateglinide plus metformin in type 2 diabetes patients with inadequate glycaemic control: an application of the CORE Diabetes Model in type 2 diabetes.

OBJECTIVES: As an example application of the CORE Diabetes Model in type 2 diabetes, we simulated the cost-effectiveness of repaglinide/metformin combination therapy versus nateglinide/metformin for treatment of individuals with type 2 diabetes with an inadequate response to sulphonylurea, metformin, or fixed dose glyburide/metformin. METHODS: The CORE Diabetes Model was used to simulate long-term outcomes for a cohort of individuals with type 2 diabetes treated with either repaglinide/metformin or nateglinide/metformin. HbA1c changes for each regimen were taken from a comparative study. At the end of the study, changes in HbA1c from baseline were -1.28% points and -0.67% points for repaglinide/metformin and nateglinide/metformin, respectively. Median final doses were 5.0 mg/day for repaglinide, 360 mg/day for nateglinide and 2000 mg/day metformin in each treatment arm. Costs were calculated as the annual costs for drugs plus costs of complications (US Medicare perspective) over a 30-year period. Life expectancy (LE) and quality-adjusted life expectancy (QALE) were calculated. Outcomes and costs were discounted at 3% annually. RESULTS: With repaglinide/metformin, improved glycaemic control led to projected decreases in complication rates, improvement of LE and QALE by 0.15 and 0.14 years respectively, and total cost savings of 3,662 dollars/person over the 30-year period. Repaglinide/metformin had a 96% probability that the incremental costs per quality-adjusted life year gained would be 20,000 dollars or less, and a 66% probability that repaglinide/metformin would be cost-saving compared to nateglinide/metformin. Sensitivity analyses supported the validity and reliability of the results. CONCLUSIONS: In the health economic context, repaglinide/metformin combination was dominant to nateglinide/metformin. The CORE Diabetes Model is a tool to help third-party reimbursement payers identify treatments for type 2 diabetes that are good value for money.

Carbamates↗
PubMed2005

Efficacy of once- or twice-daily extended release metformin compared with thrice-daily immediate release metformin in type 2 diabetes mellitus.

BACKGROUND: The extended-release formulation of metformin (MXR) prolongs drug absorption in the upper gastrointestinal tract and permits once-daily dosing in patients with type 2 diabetes mellitus (T2DM). This newer formulation may enhance patient compliance with oral therapy compared to conventional immediate-release metformin (MIR) in T2DM. OBJECTIVES: To analyse whether a switch from thrice daily MIR to once or twice daily MXR wouldachieve comparable degrees of glycemic control in patients with type 2 diabetes mellitus (T2DM). METHODS: We conducted an open study of the efficacy and tolerability of MXR in 40 patients with T2DM who had achieved moderate or good glycemic control with MIR alone or in combination with other antihyperglycemic agents. After a lead in period of 3 months patients were switched over to a specific brand of MIR at baseline (Visit 0). Patients were subsequently followed for 4 more visits. These visits were done monthly, after taking MIR in a dose of 1-2 g/day (Visit 1); MXR as a single dose at dinner but 0.5 g less than baseline dose of MIR (Visit 2); MXR, 1-2 g/day as a single dose at bedtime, with strength same as that of baseline dose of MIR (Visit 3); and MXR, 1-2 g/day in two divided doses keeping dose same as baseline MIR (Visit 4). Glycemic control was assessed by a four-point glucose profile (fasting and three postprandial levels) at each visit. RESULTS: At visit 2, when patients had been on 500 mg lesser dose of MXR for 1 month, glucose profile worsened. However, glycemic control, at visit 3, returned to earlier levels when dose of MXR was increased back to original dose. Overall the MXR formulation was well tolerated with minor gastrointestinal adverse effects, reported by only 3 patients. CONCLUSION: Patients with T2DM who had been receiving thrice-daily MIR achieved comparable glycemic control when therapy was switched to once- or twice-daily MXR at the same total daily dose.

Adult↗
PubMed2005

Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study.

OBJECTIVE: This study was designed to compare the efficacy, safety and tolerability of rosiglitazone (RSG) added to submaximal doses of metformin (MET) with dose escalation to the maximal effective dose of MET monotherapy in type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: In this multi-center, double-blind, randomized, parallel-group study, 766 subjects with a baseline MET dose of 1000 mg/day were randomized to receive either RSG 4 mg/day (4 mg/1000 mg) or MET 500 mg/day (1500 mg/day total dose) for 8 weeks. Only the RSG dose was increased in the combination group - to 8 mg/day (8 mg/1000 mg) - and only the MET dose was increased in the MET monotherapy group - to 2000 mg/day for the remaining 16 weeks. RESULTS: After 24 weeks, RSG added to MET (8 mg/1000 mg/day) was at least as effective as 2000 mg/day of MET in improving HbA(1c), with mean reductions of -0.93% (95% CI: -1.06%, -0.80%) and -0.71% (95% CI: -0.83%, -0.60%), respectively, from baseline in subjects that completed the study according to the investigator (mean treatment effect/difference of -0.20% [95% CI: -0.36%, -0.04%]). In addition, a higher percentage of subjects in the RSG + MET group achieved American Diabetes Association target levels of HbA(1c) < 7% (58.1% versus 48.4%) and American Association of Clinical Endocrinologists target levels of HbA(1c) <or= 6.5% (40.9% versus 28.2%). This combination provided significantly greater reductions from baseline in fasting plasma glucose (FPG; -2.29 mmol/L [+/- 2.37 mmol/L] and -1.12 mmol/L [+/- 2.41 mmol/L], respectively), with a treatment difference of -0.85 mmol/L (95% Cl: -1.23 mmol/L, -0.47 mmol/L). For the intent-to-treat (ITT) population, the percentage of subjects experiencing a gastrointestinal side-effect was 27.9% and 38.7% for the RSG + MET and MET groups, respectively (OR = 1.63, 95% CI: 1.19, 2.24). Mean body weight (+/- SD) increased in all randomized subjects treated with the combination therapy (+ 1.79 +/- 4.15 kg) compared with a mean weight loss in the up-titrated MET group (-1.78 +/- 3.50 kg). CONCLUSIONS: This study suggests that addition of RSG to submaximal doses of MET may be a suitable alternative to the maximal effective dose of MET monotherapy.

Adolescent↗
PubMed2004

Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of metformin at the start and after more than one year of therapy.

Flutamide (Flu)-metformin (Met) with ethinylestradiol-drospirenone is a combination therapy that reduces the total and abdominal fat excess, diminishes the lean mass deficit, and attenuates the dysadipocytokinemia of young and nonobese women with ovarian hyperandrogenism, a variant of polycystic ovary syndrome. We have now questioned the need: 1) to add Met at the start of Flu plus ethinylestradiol-drospirenone; and 2) to maintain Met after more than 1 yr on full combination therapy. The additive effects of Met (850 mg/d) were assessed in studies A and B, over 3 months, in young patients with hyperinsulinemic hyperandrogenism. In study A, all participants [n = 31; age approximately 16 yr; body mass index approximately 22 kg/m(2)] started on Flu (62.5 mg/d) and an oral contraceptive (ethinyl-estradiol + drospirenone), and they were randomized to receive Met in addition or not. In study B, all participants (n = 42; age approximately 19 yr; body mass index approximately 22 kg/m(2)) had been treated with Flu-Met plus the same contraceptive for a mean duration of 17 months, and they were randomized for discontinuation of Met or not. Fasting blood glucose, serum insulin, testosterone, lipid profile, adiponectin, and IL-6 were determined at the start and after 3 months, together with body composition, by dual energy x-ray absorptiometry. The results of studies A and B complemented each other; the addition of Met was found to have consistently (more) normalizing effects on IL-6 and adiponectin, on lean mass (mean Met benefit of +1.2 kg in study A and +0.6 kg in study B), and in particular on abdominal fat excess [Met benefit of -0.7 kg (A) and -0.3 kg (B)]. In conclusion, Met proved to be a pivotal component of a prime combination therapy that attenuates the dysadipocytokinemia, the lean mass deficit, and the central adiposity of young patients with polycystic ovary syndrome.

Adolescent↗