to metformin in clinical trials, there were no reports of lactic acidosis. reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. the risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. the risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin hydrochloride tablets usp and by use of the minimum effective dose of metformin hydrochloride tablets usp. in particular, treatment of the elderly should be accompanied by careful monitoring of renal function. metformin hydrochloride tablets usp treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. in addition, metformin hydrochloride tablets usp should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. because impaired hepatic function may significantly limit the ability to clear lactate, metformin hydrochloride tablets usp should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin hydrochloride tablets usp, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. in addition, metformin hydrochloride tablets usp should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also precautions). the onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. there may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. the patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also precautions). metformin hydrochloride tablets usp should be withdrawn until the situation is clarified. serum electrolytes, ketones, blood glucose, and if indicated, blood ph, lactate levels, and even blood metformin levels may be useful. once a patient is stabilized on any dose level of metformin hydrochloride tablets usp, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/l in patients taking metformin hydrochloride tablets usp do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (see also precautions.) lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). lactic acidosis is a medical emergency that must be treated in a hospital setting. in a patient with lactic acidosis who is taking metformin hydrochloride tablets usp, the drug should be discontinued immediately and general supportive measures promptly instituted. because metformin hydrochloride is dialyzable (with a clearance of up to 170 ml/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. such management often results in prompt reversal of symptoms and recovery. (see also contraindications and precautions.)

e minimum effective dose for the patient. thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. the therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin hydrochloride, either when used as monotherapy or in combination with sulfonylurea or insulin. monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. short-term administration of metformin hydrochloride may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. recommended dosing schedule adults – in general, clinically significant responses are not seen at doses below 1500 mg per day. however, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms. the usual starting dose of metformin hydrochloride is 500 mg twice a day or 850 mg once a day, given with meals. dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. for those patients requiring additional glycemic control, metformin hydrochloride may be given to a maximum daily dose of 2550 mg per day. doses above 2000 mg may be better tolerated given three times a day with meals. if higher doses of metformin are required, metformin hydrochloride should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. (see clinical pharmacology: clinical studies.) pediatrics – the usual starting dose of metformin hydrochloride is 500 mg twice a day, given with meals. dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. transfer from other antidiabetic therapy when transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin hydrochloride, no transition period generally is necessary. when transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. concomitant metformin hydrochloride and oral sulfonylurea therapy in adult patients if patients have not responded to four weeks of the maximum dose of metformin hydrochloride monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide). with concomitant metformin hydrochloride and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. in a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin hydrochloride 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin hydrochloride and glyburide, respectively, to reach the goal of glycemic control as measured by fpg, hba1c and plasma glucose response (see clinical pharmacology: clinical studies). however, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. with concomitant metformin hydrochloride and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. appropriate precautions should be taken. (see package insert of the respective sulfonylurea.) if patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin hydrochloride and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride. concomitant metformin hydrochloride and insulin therapy in adult patients the current insulin dose should be continued upon initiation of metformin hydrochloride therapy. metformin hydrochloride therapy should be initiated at 500 mg once daily in patients on insulin therapy. for patients not responding adequately, the dose of metformin hydrochloride should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. the maximum recommended daily dose is 2500 mg for metformin hydrochloride. it is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dl in patients receiving concomitant insulin and metformin hydrochloride. further adjustment should be individualized based on glucose-lowering response. specific patient populations metformin hydrochloride is not recommended for use in pregnancy. metformin hydrochloride is not recommended in patients below the age of 10 years. the initial and maintenance dosing of metformin hydrochloride should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. any dosage adjustment should be based on a careful assessment of renal function. generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin hydrochloride. monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (see warnings.)

of study medication in 6% of patients treated with metformin hydrochloride tablets usp. additionally, the following adverse reactions were reported in ≥1.0 to ≤5.0% of metformin hydrochloride tablets usp patients and were more commonly reported with metformin hydrochloride tablets usp than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. pediatric patients in clinical trials with metformin hydrochloride tablets usp in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

s approximately 50% to 60%. studies using single oral doses of metformin hydrochloride 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (cmax), a 25% lower area under the plasma concentration versus time curve (auc), and a 35-minute prolongation of time to peak plasma concentration (tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. the clinical relevance of these decreases is unknown. distribution the apparent volume of distribution (v/f) of metformin following single oral doses of metformin hydrochloride tablets usp 850 mg averaged 654 ± 358 l. metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. metformin partitions into erythrocytes, most likely as a function of time. at usual clinical doses and dosing schedules of metformin hydrochloride tablets usp, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1mcg/ml. during controlled clinical trials of metformin hydrochloride tablets usp, maximum metformin plasma levels did not exceed 5 mcg/ml, even at maximum doses. metabolism and elimination intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. renal clearance (see table 1) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. in blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. special populations patients with type 2 diabetes in the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see table 1), nor is there any accumulation of metformin in either group at usual clinical doses renal insufficiency in patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see table 1; also see warnings). hepatic insufficiency no pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. geriatrics limited data from controlled pharmacokinetic studies of metformin hydrochloride tablets usp in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and cmax is increased, compared to healthy young subjects. from these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see table 1). metformin hydrochloride tablets usp treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see warnings and dosage and administration) table 1: select mean (±s.d.) metformin pharmacokinetic parameters following single or multiple oral doses of metformin hydrochloride tablets subject groups: metformin hydrochloride tablets dosea(number of subjects) cmaxb (µg/ml) tmaxo (hrs) renal clearance (ml/min) healthy, nondiabetic adults: 500 mg single dose (24) 1.03 (±0.33) 2.75 (±0.81) 600 (±132) 850 mg single dose (74)d 1.60 (±0.38) 2.64 (±0.82) 552 (±139) 850 mg three times daily for 19 dosese (9) 2.01 (±0.42) 1.79 (±0.94) 642 (±173) adults with type 2 diabetes: 850 mg single dose (23) 1.48 (±0.5) 3.32 (±1.08) 491 (±138) 850 mg three times daily for 19 dosese (9) 1.90 (±0.62) 2.01 (±1.22) 550 (±160) elderlyf , healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) renal-impaired adults: 850 mg single dose mild (clcrg 61-90 ml/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122) moderate (clcr 31-60 ml/ min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57) severe (clcr 10-30 ml/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90) a all doses given fasting except the first 18 doses of the multiple dose studies b peak plasma concentration c time to peak plasma concentration d combined results (average means) of five studies: mean age 32 years (range 23-59 years) e kinetic study done following dose 19, given fasting f elderly subjects, mean age 71 years (range 65-81 years) g clcr = creatinine clearance normalized to body surface area of 1.73 m2 pediatrics after administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin cmax and auc differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function. gender metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets usp was comparable in males and females. race no studies of metformin pharmacokinetic parameters according to race have been performed. in controlled clinical studies of metformin hydrochloride tablets usp in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and hispanics (n=24). clinical studies metformin hydrochloride tablets usp in a double-blind, placebo-controlled, multicenter u.s. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [fpg] of approximately 240 mg/dl), treatment with metformin hydrochloride tablets usp (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (ppg) and hemoglobin a1c (hba1c of 59 mg/dl, 83 mg/dl, and 1.8%, respectively, compared to the placebo group (see table 2) table 2: metformin hydrochloride tablets vs placebo summary of mean changes from baseline* in fasting plasma glucose, hba1c, and body weight, at final visit (29-week study) metformin hydrochloride tablets placebo p–value (n=141) (n=145) fpg (mg/dl) baseline 241.5 237.7 ns** change at final visit -53.0 6.3 0.001 hemoglobin a1c (%) baseline 8.4 8.2 ns** change at final visit -1.4 0.4 0.001 body weight (lbs) baseline 201.0 206.0 ns**t change at final visit -1.4 -2.4 ns** *all patients on diet therapy at baseline **not statistically significant a 29-week, double-blind, placebo-controlled study of metformin hydrochloride tablets usp and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline fpg of approximately 250 mg/dl) (see table 3). patients randomized to the combination arm started therapy with metformin hydrochloride tablets usp 500 mg and glyburide 20 mg. at the end of each week of the first four weeks of the trial, these patients had their dosages of metformin hydrochloride tablets usp increased by 500 mg if they had failed to reach target fasting plasma glucose. after week four, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin hydrochloride tablets usp 2500 mg. patients in the metformin hydrochloride tablets usp only arm (metformin plus placebo) followed the same titration schedule. at the end of the trial, approximately 70% of the patients in the combination group were taking metformin hydrochloride tablets usp 2000 mg/glyburide 20 mg or metformin hydrochloride tablets usp 2500 mg/glyburide 20 mg. patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in fpg, ppg, and hba1c of 14 mg/dl, 3 mg/dl, and 0.2%, respectively. in contrast, those randomized to metformin hydrochloride tablets usp (up to 2500 mg/day) experienced a slight improvement, with mean reductions in fpg, ppg, and hba1c of 1 mg/dl, 6 mg/dl, and 0.4%, respectively. the combination of metformin hydrochloride tablets usp and glyburide was effective in reducing fpg, ppg, and hba1clevels by 63 mg/dl, 65 mg/dl, and 1.7%, respectively. compared to results of glyburide treatment alone, the net differences with combination treatment were -77 mg/dl, - 68 mg/dl, and -1.9%, respectively (see table 3) table 3: combined metformin hydrochloride tablets /glyburide (comb) vs glyburide (glyb) or metformin hydrochloride tablets (met) monotherapy: summary of mean changes from baseline* in fasting plasma glucose, hba1c, and body weight, at final visit (29-week study) comb (n=213) glyb (n=209) met (n=210) p-values glyb vs comb met vs comb met vs glyb fasting plasma glucose (mg/dl) baseline 250.5 247.5 253.9 ns** ns** ns** change at final visit -63.5 13.7 -0.9 0.001 0.001 0.025 hemoglobin a1c (%) baseline 8.8 8.5 8.9 ns** ns** 0.007 change at final visit -1.7 0.2 -0.4 0.001 0.001 0.001 body weight (lbs) baseline 202.2 203.0 204.0 ns** ns** ns** change at final visit 0.9 -0.7 -8.4 0.011 0.001 0.001 *all patients on glyburide, 20 mg/day, at baseline **not statistically significant the magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride tablets usp therapy was proportional to the level of fasting hyperglycemia. patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin. in clinical studies, metformin hydrochloride tablets usp, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and ldl cholesterol levels and had no adverse effects on other lipid levels (see table 4). table 4: summary of mean percent change from baseline of major serum lipid variables at final visit (29-week studies) metformin hydrochloride tablets vs placebo combined metformin hydrochloride tablets /glyburide vs monotherapy metformin hydrochloride tablets (n=141) placebo (n=145) metformin hydrochloride tablets (n=210) metformin hydrochloride tablets/ glyburide (n=213) glyburide (n=209) total cholesterol (mg/dl) baseline 211.0 212.3 213.1 215.6 219.6 mean % change at final visit -5% 1% -2% -4% 1% total triglycerides (mg/dl) baseline 236.1 203.5 242.5 215.0 266.1 mean % change at final visit -16% 1% -3% -8% 4% ldl-cholesterol (mg/dl) baseline 135.4 138.5 134.3 136.0 137.5 mean % change at final visit -8% 1% -4% -6% 3% hdl-cholesterol (mg/dl) baseline 39.0 40.5 37.2 39.0 37.0 mean % change at final visit 2% -1% 5% 3% 1% in contrast to sulfonylureas, body weight of individuals on metformin hydrochloride tablets usp tended to remain stable or even decrease somewhat (see tables 2 and 3). a 24-week, double-blind, placebo-controlled study of metformin hydrochloride tablets usp plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see table 5). patients randomized to receive metformin hydrochloride tablets usp plus insulin achieved a reduction in hba1c of 2.10%, compared to a 1.56% reduction in hba1c achieved by insulin plus placebo. the improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 u/day vs 110.6 u/day, metformin hydrochloride tablets usp plus insulin versus insulin plus placebo, respectively, p=0.04 table 5: combined metformin hydrochloride tablets /insulin vs placebo/insulin summary of mean changes from baseline in hba1c and daily insulin dose metformin hydrochloride tablets/ insulin (n=26) placebo/ insulin (n=28) treatment difference mean ± se hemoglobin a1c (%) baseline 8.95 9.32 change at final visit -2.10 -1.56 -0.54 ± 0.43a insulin dose (u/day) baseline 93.12 94.64 change at final visit -0.15 15.93 -16.08 ± 7.77b a statistically significant using analysis of covariance with baseline as covariate (p=0.04) not significant using analysis of variance (values shown in table) b statistically significant for insulin (p=0.04) a second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average hba1c of 7.46 ± 0.97%, the addition of metformin hydrochloride tablets usp maintained similar glycemic control (hba1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin hydrochloride tablets usp plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin hydrochloride tablets usp plus insulin and placebo plus insulin, p<0.01). in addition, this study demonstrated that the combination of metformin hydrochloride tablets usp plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01. a 24-week, double-blind, randomized study of metformin hydrochloride tablets usp, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets usp 500 mg twice daily for at least 8 weeks prior to study entry. the metformin hydrochloride tablets usp dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. patients qualified for the study if hba1cwas ≤8.5% and fpg was ≤200 mg/dl. changes in glycemic control and body weight are shown in table 6 table 6: summary of mean changes from baseline* in hba1c, fasting plasma glucose, and body weight at week 12 and at final visit (24-week study) metformin hydrochloride tablets 500 mg twice daily hemoglobin a1c (%) (n=67) baseline 7.06 change at 12 weeks 0.14 (95% ci) (-0.03, 0.31) change at final visit 0.14a (95% ci) (-0.04, 0.31) fpg (mg/dl) (n=69) baseline 127.2 change at 12 weeks 12.9 (95% ci) (6.5, 19.4) change at final visit 14.0 (95% ci) (7.0, 21.0) body weight (lbs) (n=71) baseline 210.3 change at 12 weeks 0.4 (95% ci) (-0.4, 1.5) change at final visit 0.9 (95% ci) (-0.4, 2.2) *all patients on metformin hydrochloride tablets 500mg twice daily at baseline a n=68 changes in lipid parameters in the previously described study of metformin hydrochloride tablets usp are shown in table 7 table 7: summary of mean percent changes from baseline* in major lipid variables at final visit (24-week study) metformin hydrochloride tablets 500mg twice daily total cholesterol (mg/dl) (n=68) baseline 199.0 mean % change at final visit 0.1% total triglycerides (mg/dl) (n=68) baseline 178.0 mean % change at final visit 6.3% ldl-cholesterol (mg/dl) (n=68) baseline 122.1 mean % change at final visit -1.3% hdl-cholesterol (mg/dl) (n=68) baseline 41.9 mean % change at final visit 4.8% *all patients on metformin hydrochloride tablets 500mg twice daily at baseline pediatric clinical studies in a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean fpg 182.2 mg/dl), treatment with metformin hydrochloride tablets usp (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in fpg of 64.3 mg/dl, compared with placebo (see table 8) table 8: metformin hydrochloride tablets vs placebo (pediatricsa) summary of mean changes from baseline* in plasma glucose and body weight at final visit metformin hydrochloride tablets placebo p-value fpg (mg/dl) (n=37) (n=36) baseline 162.4 192.3 change at final visit -42.9 21.4 <0.001 body weight (lbs) (n=39) (n=38) baseline 205.3 189.0 change at final visit -3.3 -2.0 ns** apediatric patients mean age 13.8 years (range 10 to 16 years) * all patients ondiet therapy at baseline ** not statistically significant

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