Beruflich Dokumente
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68:20.04 Biguanides
Metformin Hydrochloride
Introduction
C4 H11N5 HCl
Metformin hydrochloride is a biguanide antidiabetic agent.1 , 2 , 3 , 4 , 18, 20, 22, 23, 27,
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Uses
Diabetes Mellitus
Metformin is used as monotherapy as an adjunct to diet and exercise for the
management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) in patients
whose hyperglycemia cannot be controlled by diet alone.1 , 3 , 4 , 6 , 8 , 15, 16, 17, 18, 19,
20 27 29 95 166 243 245 246
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Metformin may also be used in combination with a
sulfonylurea or a thiazolidinedione antidiabetic agent as an adjunct to diet and exercise
in patients with type 2 diabetes who do not achieve adequate glycemic control with
metformin, sulfonylurea, or thiazolidinedione monotherapy.1 , 3 , 6 , 15, 18, 20, 22, 27, 29,
30 48 59 78 88 95 97 99 112 134 166 191 234 237 239 241 242 243 245 246 250
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Metformin may be used with repaglinide in patients with type 2 diabetes mellitus who
have inadequate glycemic control with diet, exercise, and monotherapy with metformin,
a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent.238, 249 Metformin
also may be used concomitantly with nateglinide in patients who no longer respond
adequately to metformin despite appropriate diet, exercise, and metformin
monotherapy. Metformin is commercially available in fixed combination with glyburide or
glipizide for use as initial therapy in the management of patients with type 2 diabetes
mellitus whose hyperglycemia cannot be controlled by diet and exercise alone, or as
second-line therapy in patients who do not achieve adequate control of hyperglycemia
despite therapy with diet, exercise, and initial treatment with a sulfonylurea antidiabetic
agent or metformin. A thiazolidinedione may be added to metformin in fixed combination
with glyburide in patients who have inadequate glycemic control with fixed-combination
therapy. Metformin is commercially available in fixed combination with rosiglitazone for
the management of type 2 diabetes mellitus in patients who who have inadequate
glycemic control with metformin monotherapy or are already receiving therapy with
metformin and rosiglitazone as separate components. Metformin also may be used as
adjunctive therapy in patients with type 2 diabetes mellitus receiving insulin therapy to
improve glycemic control and/or decrease the dosage of insulin needed to obtain
optimal glycemic control.
The National Diabetes Data Group and the American Diabetes Association (ADA)
The DCCT was terminated prematurely because of the pronounced benefits of intensive
insulin regimens,182, 255 and all treatment groups were encouraged to institute or
continue such intensive insulin therapy.255 In the Epidemiology of Diabetes
Interventions and Complications (EDIC) study, the long-term, open-label continuation
phase of the DCCT, the reduction in the risk of microvascular complications (e.g.,
retinopathy, nephropathy, neuropathy) associated with intensive insulin therapy has
been maintained throughout 7 years of follow-up.255 In addition, the prevalence of
hypertension (an important consequence of diabetic nephropathy) in those receiving
conventional therapy has exceeded that of those receiving intensive therapy.255
Patients receiving conventional insulin therapy in the DCCT were able to achieve a
lower glycosylated hemoglobin when switched to intensive therapy in the continuation
study, although the average glycosylated hemoglobin values achieved during the
continuation study were higher (i.e., worse) than those achieved during the DCCT with
intensive insulin therapy.255 Patients who remained on intensive insulin therapy during
the EDIC continuation study were not able to maintain the degree of glycemic control
achieved during the DCCT; by 5 years of follow-up in the EDIC study, glycosylated
hemoglobin values were similar in both intensive and conventional therapy groups.255
The EDIC study demonstrated that the greater the duration of chronically elevated
plasma glucose concentrations (as determined by glycosylated hemoglobin values), the
greater the risk of microvascular complications.255 Conversely, the longer patients can
maintain a target glycosylated hemoglobin of 7% of less, the greater the delay in the
onset of these complications.255
In another randomized, controlled study (Stockholm Diabetes Intervention Study) in
patients with type 1 diabetes mellitus who were evaluated for up to 7.5 years, blood
glucose control (as determined by glycosylated hemoglobin concentrations) was
improved, and the incidence of microvascular complications (e.g., decreased visual
acuity, retinopathy, nephropathy, decreased nerve conduction velocity) reduced, with
intensive insulin treatment (e.g., at least 3 insulin injections daily accompanied by
intensive educational efforts) compared with that in patients receiving standard
treatment (e.g., generally 2 insulin injections daily without intensive educational
efforts).190
Evidence from the United Kingdom Prospective Diabetes (UKPD) study216, 218, 219, 220
and other smaller studies51 in patients with type 2 diabetes mellitus generally is
consistent with the same benefits of oral hypoglycemic agents on microvascular
complications as those observed in type 1 diabetics receiving insulin therapy in the
DCCT. 182, 186, 216, 218, 219, 220, 221 The UKPD study evaluated more than 5000
middle-aged, newly diagnosed, overweight (exceeding 120% of ideal body weight) or
non-overweight patients with type 2 diabetes mellitus who received conventional or
intensive treatment regimens with an oral sulfonylurea agent and/or insulin; overweight
patients also could be allocated to metformin therapy in the same proportions as those
allocated to sulfonylureas and insulin.218, 219, 220, 222 Initial therapy consisted of an
oral antidiabetic agent (sulfonylurea or metformin) or insulin, with stepwise addition of
metformin (or glyburide in those initially allocated to metformin) in those poorly
controlled on initial therapy or conversion to insulin alone in patients not adequately
controlled with 2 oral agents.218, 219, 220, 222 Intensive treatment consisted of
antidiabetic therapy targeted to a fasting plasma glucose concentration of less than 108
mg/dL or, in patients receiving insulin, preprandial glucose concentrations of 72-126
mg/dL. 218, 219, 220, 222 Conventional treatment consisted of antidiabetic therapy
targeted to a fasting plasma glucose concentration of less than 270 mg/dL without
symptoms of hyperglycemia.218, 219, 220, 222 Results of the UKPD study indicate
beneficial effects on retinopathy, nephropathy, and possibly neuropathy with intensive
glucose-lowering therapy in type 2 diabetics, in whom a median glycosylated
hemoglobin of 7% was achieved compared with a value of 7.9% in the conventional
treatment group.219, 220 The overall incidence of microvascular complications was
reduced by 25% with intensive therapy.219, 200 Epidemiologic analysis of the UKPD
study results indicates a continuous relationship between the risks of microvascular
complications and glycemia, with a 35% reduction in risk for each 1% reduction in
glycosylated hemoglobin.219, 220 While an association between the risk of
macrovascular (e.g., cardiovascular) complications was also demonstrated by the
UKPD study, there was no statistically significant effect of lowering blood glucose on
cardiovascular complications.219, 220
In the UKPD study, fasting plasma glucose concentrations and percent glycosylated
hemoglobin values steadily increased over 10 years in the patients receiving
conventional therapy, and more than 80% of these patients eventually required
antidiabetic therapy in addition to diet to maintain fasting plasma glucose concentrations
within the desired goal of less than 270 mg/dL.216, 219, 220, 222 In patients receiving
intensive therapy initiated with chlorpropamide, glyburide, or insulin, fasting plasma
glucose concentrations and percent glycosylated hemoglobin values decreased during
the first year of the study.217, 219, 222 Subsequent increases in these indices of
glycemic control after the first year paralleled that in the conventional therapy group for
the remainder of the study, indicating slow decline of pancreatic -cell function and loss
of glycemic control regardless of intensity of therapy. 217, 219, 223, 224
The ADA currently recommends the same blood glucose and glycosylated hemoglobin
goals for all patients with type 1 or type 2 diabetes mellitus but states that less stringent
treatment goals may be appropriate for certain individuals.14 Based on target values for
blood glucose and glycosylated hemoglobin used in clinical trials (e.g., DCCT) for type 1
diabetic patients,182 modified somewhat to reduce the risk of severe hypoglycemia,
ADA currently recommends target preprandial (fasting) and peak postprandial plasma
glucose concentrations of 90-130 and less than 180 mg/dL, respectively, and
glycosylated hemoglobin concentrations of less than 7% (based on a nondiabetic range
of less than 6%) in patients with type 1 or 2 diabetes mellitus who are not pregnant. 14
Patients with diabetes mellitus who have elevated glycosylated hemoglobin
concentrations despite having adequate preprandial glucose concentrations should
monitor glucose concentrations 1-2 hours after the start of a meal.14 Treatment with
agents (e.g., a-glucosidase inhibitors) that principally lower postprandial glucose
concentrations to within target ranges also should reduce glycosylated hemoglobin.14,
244
The effect of adequate control of postprandial glucose concentrations on the
microvascular and macrovascular complications of diabetes mellitus is not known.14
Treatment goals should be individualized, and specific target values for blood glucose
and glycosylated hemoglobin appropriately adjusted, based on the patient's capacity to
understand and adhere to the treatment regimen, the risk of severe hypoglycemia, and
other patient factors that may increase risk or decrease benefit (e.g., very young or old
age, comorbid conditions, other diseases that materially shorten life expectancy).14
Strict glycemic control (e.g., maintenance of fasting blood glucose concentrations below
140 mg/dL) usually is not achieved in patients with type 2 diabetes mellitus who have
moderately severe to severe hyperglycemia prior to therapy; most patients with a
baseline fasting blood glucose concentration exceeding 200 mg/dL are unlikely to
experience a return to euglycemia with oral antidiabetic agent monotherapy.18, 78, 105,
134 146
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Data from the long-term UKPD study in middle-aged, newly diagnosed patients with
type 2 diabetes mellitus indicate that strict glycemic control (i.e., maintenance of fasting
blood glucose concentrations below 108 mg/dL) was not achieved with initial intensive
oral antidiabetic therapy in most patients; at 3 and 9 years, 50 and 75%, respectively, of
patients required combination therapy with sulfonylureas or initiation of insulin to
maintain adequate glycemic control.216, 220, 223, 231 While strict guidelines for insulin
dosage adjustments were used in the DCCT study, adjustments of antidiabetic therapy
dosage in the UKPD study were not as frequent (dosage adjustments allowed every 3
months); in addition, the definition of secondary treatment failure with sulfonylureas and
the time of institution of supplementary antidiabetic therapy changed as the study
progressed.182, 216, 219, 223, 225
Considerations in Initiating and Maintaining Antidiabetic Therapy
When initiating therapy for patients with type 2 diabetes mellitus who do not have
severe symptoms, diet should be emphasized as the primary form of treatment;10, 14,
18 24 25 95 123
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caloric restriction and weight reduction are essential in obese
14 24 25 26 88 95 123
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Although appropriate dietary management and weight
reduction alone may be effective in controlling blood glucose concentration and
symptoms of hyperglycemia, many patients receiving dietary advice fail to achieve and
maintain adequate glycemic control with dietary modification alone.13, 23, 24, 25, 26, 95,
134 146 184
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The importance of regular physical activity also should be emphasized, and
cardiovascular risk factors should be identified and corrective measures employed when
feasible.10, 14, 26 Efforts also should be aimed at blood pressure control, as reduction in
blood pressure to a mean of 144/82 mm Hg ("tight blood pressure control") in patients
with diabetes mellitus and uncomplicated mild to moderate hypertension in the UKPD
study substantially reduced the incidence of virtually all macrovascular (e.g., stroke,
heart failure) and microvascular (e.g., retinopathy, vitreous hemorrhage, renal failure)
outcomes and diabetes-related mortality.14, 217, 220, 222, 225, 228, 229
If this treatment program (dietary management, weight reduction, exercise, reduction of
cardiovascular risk factors) fails to reduce symptoms and/or blood glucose
concentrations within 2-3 months of diagnosis, initiation of monotherapy with an oral
antidiabetic agent (e.g., sulfonylurea, metformin, acarbose) or insulin should be
considered.10, 14, 15, 18, 19, 26, 72, 88, 95, 105, 113, 179 The patient and physician should
recognize that dietary management is the principal consideration in the management of
diabetes mellitus, and that oral antidiabetic therapy is used only as an adjunct to, and
not as a substitute for or a convenient means to avoid, proper dietary management.30,
95 189 191 192
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In addition, loss of blood glucose control on diet alone can be temporary
in some patients, requiring only short-term management with drug therapy.1 , 134, 243,
245 246
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Metformin Monotherapy
Clinical studies indicate that metformin is as effective as a sulfonylurea antidiabetic
agent (e.g., chlorpropamide,3 , 16, 17, 18, 19, 27, 29 glyburide,15, 18, 19, 27, 29, 45, 46, 57,
78
glipizide,18 tolbutamide3 , 48, 118) for the management of type 2 diabetes mellitus.
Although metformin often has been used in patients who did not achieve adequate
glycemic control with sulfonylurea monotherapy and who did not have symptoms of
severe insulin deficiency (e.g., ketosis, uncontrolled weight loss),6 , 15, 18, 22, 48, 59, 78,
95 112 123 146 166
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either a sulfonylurea or metformin may be used as initial
monotherapy in patients with type 2 diabetes whose hyperglycemia is not controlled
despite dietary modification and exercise.1 , 15, 18, 19, 72, 88, 95, 105, 146, 243, 245, 246
Potential advantages of metformin compared with sulfonylurea antidiabetic agents or
insulin include a minimal risk of hypoglycemia, more favorable effects on serum lipids,
reduction of hyperinsulinemia, and weight loss or lack of weight gain.1 , 2 , 3 , 6 , 16, 17, 18,
19 20 27 30 42 60 68 102 134 146 166
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Type 2 diabetic patients who are very obese or
who have baseline fasting blood glucose concentrations exceeding 200 mg/dL may be
less likely to respond to therapy with sulfonylurea antidiabetic agents.197, 198 Therefore,
since metformin may stabilize or even decrease body weight,1 , 3 , 4 , 6 , 8 , 16, 17, 18, 19,
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the drug may be particularly useful as initial
monotherapy in obese individuals who might gain weight while receiving a
sulfonylurea.15, 16, 17 Metformin is equally effective in lean or obese patients with type 2
diabetes mellitus. 3 , 6 , 15, 16, 17, 18, 19, 31, 46, 105, 146 Metformin may be effective as
replacement monotherapy in some patients with primary or secondary failure to
sulfonylureas.1 , 30, 48, 78, 95, 134, 179 (See Diabetes Mellitus: Combination Therapy, in
Uses.)
In controlled studies of up to 8 months' duration in adults with type 2 diabetes mellitus,
therapy with metformin hydrochloride (0.5-3 g daily) reduced fasting and postprandial
glucose concentrations15, 31, 34, 35, 42, 60, 78, 85, 105 and glycosylated hemoglobin15,
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substantially more than did placebo. The antihyperglycemic effect of
metformin does not appear to correlate with duration of diabetes, age, obesity, race,
fasting insulin concentrations, or baseline plasma lipid concentrations.6 , 20, 78, 105 In a
placebo-controlled study in pediatric (10-16 years of age), treatment-naive (i.e., those
receiving diet therapy only), obese patients with type 2 diabetes mellitus, the net
difference in fasting plasma glucose concentrations in patients receiving metformin
hydrochloride (up to 2 g daily) or placebo for up to 16 weeks was 64.3 mg/dL, reflecting
an increase in fasting plasma glucose concentrations in the placebo group and an
improvement in glycemic control with metformin therapy. 1 The improvement in glycemic
control with metformin in these pediatric patients was similar to that observed in clinical
studies with the drug in adults.1 A small, similar weight loss occurred in patients
receiving either metformin or placebo in this study.1 In a multicenter, randomized,
controlled study in newly diagnosed, asymptomatic patients with type 2 diabetes
mellitus, the efficacy of metformin therapy in reducing fasting plasma glucose (target
value: less than 108 mg/dL) and glycosylated hemoglobin concentrations in a subgroup
of obese patients was similar to that of therapy with a sulfonylurea (chlorpropamide,
glyburide, or glipizide) or insulin in nonobese patients; all drug regimens improved
glycemic control compared with conventional (diet only) therapy.19, 166, 184 However,
unlike sulfonylurea or insulin therapy, metformin therapy generally decreased plasma
insulin concentrations and was not associated with weight gain or an increased
incidence of hypoglycemia.19, 166, 184 In this long-term study, gradual deterioration in
glycemic control occurred with all therapies over the study period despite increases in
drug dosage or combined drug therapy; glycosylated hemoglobin concentrations
generally had increased to baseline levels after 4-5 years of therapy with any of the drug
regimens. 184 Such deterioration in glycemic control has been attributed to a progressive
decline in pancreatic -cell function94, 95, 146, 166, 184 rather than a reduction in insulin
sensitivity.166
Combination Therapy
Metformin may be used concomitantly with one or more oral antidiabetic agents (e.g., a
sulfonylurea, a thiazolidinedione, a meglitinide, and/or an a-glucosidase inhibitor) or
insulin to improve glycemic control in patients with type 2 diabetes.1 , 3 , 6 , 15, 18, 20, 22,
27 29 30 48 59 78 88 90 94 95 97 99 112 134 146 166 191 237 238 239 240 241
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While metformin may be effective as replacement monotherapy in some patients who
develop primary or secondary failure to sulfonylurea antidiabetic agents, optimum
benefit generally is obtained by addition of metformin to existing sulfonylurea therapy as
soon as monotherapy no longer provides adequate glycemic control (i.e., before primary
or secondary failure with symptomatic hyperglycemia occurs).1 , 30, 48, 78, 95, 134, 179,
239 243 245 246
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Primary or secondary failure may occur with metformin as well as with
sulfonylurea therapy.6 , 16, 17, 18, 27, 78, 95, 99, 146, 166 In patients receiving initial
monotherapy with metformin, the incidence of primary and secondary failures appears
to be less than6 , 27, 166 or similar to6 , 16, 17, 18, 122 that in patients receiving
sulfonylurea monotherapy. Secondary failure to sulfonylurea antidiabetic agents or
metformin is characterized by progressively decreasing diabetic control following 1
month to several years of good control. 30, 134, 166, 184, 199 Combined therapy with
metformin and another oral antidiabetic agent generally is used in patients with
longstanding type 2 diabetes mellitus who have poor glycemic control with
monotherapy;15, 72, 95, 99, 216, 238, 240 the sequence in which metformin or a
sulfonylurea is used at initiation of therapy does not appear to alter the effectiveness of
combined therapy with the drugs.15, 95, 146
Metformin is commercially available in fixed combination with glyburide or glipizide for
use as initial therapy in the management of patients with type 2 diabetes mellitus whose
hyperglycemia cannot be controlled by diet and exercise alone. 234, 254 In several
comparative trials in such patients, therapy with metformin in fixed combination with
glyburide or glipizide was more effective in improving glycemic control (as determined
by glycosylated hemoglobin values, fasting plasma glucose concentrations) than
monotherapy with either component. 234, 254 A greater percentage of patients receiving
metformin in fixed combination with glipizide or glipizide achieved strict glycemic control
(e.g., glycosylated hemoglobin values less than 7%)14 than patients receiving
monotherapy with metformin, glyburide, or glipizide.234, 254
Metformin in fixed combination with glyburide or glipizide also is used to improve
glycemic control in patients with type 2 diabetes who are inadequately controlled with
either sulfonylurea or metformin monotherapy. 234, 254 In several comparative studies in
such patients, greater glycemic control (as determined by glycosylated hemoglobin
values, fasting plasma glucose concentrations) was achieved with the fixed combination
of metformin and glyburide or glipizide than with metformin, glyburide, or glipizide
monotherapy. 234, 254 Strict glycemic control (e.g., glycosylated hemoglobin values less
249
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patients with type 2 diabetes mellitus whose blood glucose is not adequately controlled
with either glyburide or glipizide (or another sulfonylurea antidiabetic agent) or
metformin alone.234, 254 The recommended initial dosage of the commercially available
fixed-combination tablets in previously treated patients is 500 mg of metformin
hydrochloride and 2.5 or 5 mg of glyburide or glipizide twice daily with the morning and
evening meals. 234, 254 In order to minimize the risk of hypoglycemia, the initial dosage
of glyburide and metformin hydrochloride in fixed combination should not exceed the
daily dosage of metformin hydrochloride, glyburide, or glipizide (or the equivalent
dosage of another sulfonylurea) previously received.234, 254 The dosage of the fixed
combination of metformin hydrochloride and glyburide or glipizide should be titrated
upward in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of
glyburide or glipizide until adequate control of blood glucose is achieved or a maximum
daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide or glipizide is
reached. 234, 254
For patients being switched from combined therapy with separate preparations, the
initial dosage of the fixed-combination preparation of glyburide or glipizide and
metformin hydrochloride should not exceed the daily dosage of glyburide, glipizide (or
equivalent dosage of another sulfonylurea antidiabetic agent), and metformin
hydrochloride currently being taken.234, 254 Such patients should be monitored for signs
and symptoms of hypoglycemia following the switch.234, 254 In the transfer from
previous antidiabetic therapy to fixed combination of metformin hydrochloride, the
decision to switch to the nearest equivalent dosage or to titrate dosage should be based
on clinical judgment. 254 Hypoglycemia and hyperglycemia are possible in such patients,
and any change in the therapy of type 2 diabetic patients should be undertaken with
caution and appropriate monitoring.234 If blood glucose concentrations are not
adequately controlled following initial administration of the fixed-combination
preparation, the dose may be titrated in increments of no more than 5 mg of glyburide
and 500 mg of metformin hydrochloride until adequate control of blood glucose is
achieved or a maximum dosage of 20 mg of glyburide or glipizide and 2 g of metformin
hydrochloride is reached.234, 254 The safety and efficacy of switching from another
combined therapy with separate preparations of glyburide (or another sulfonylurea
antidiabetic agent) and metformin in the fixed-combination preparation have not been
established in clinical studies.234
For patients whose hyperglycemia is not adequately controlled on therapy with
metformin in fixed combination with glyburide, a thiazolidinedione (e.g., pioglitazone,
rosiglitazone) may be added at its recommended initial dosage and the dosage of the
fixed combination may be continued unchanged. 234 In patients requiring further
glycemic control, the dosage of the thiazolidinedione may be titrated upward, based on
the dosage regimen recommended by the manufacturer. 234 Triple therapy with
glyburide, metformin, and a thiazolidinedione may increase the potential for
hypoglycemia at any time of day.234 If hypoglycemia develops during such triple
therapy, consideration should be given to reducing the dosage of the glyburide
component; adjustment of the dosage of the other components of the antidiabetic
regimen also should be considered as clinically indicated.234
Therapy with metformin in fixed combination with glyburide should be used with caution
in geriatric patients, since aging is associated with reduced renal function.234 The initial
and maintenance dosages of metformin hydrochloride in fixed combination with
glyburide should be conservative and should be titrated carefully in such patients.234
Renal function should be assessed with initial dosage selection and with each dosage
adjustment, particularly in geriatric patients, to aid in prevention of lactic acidosis. 234 To
minimize the risk of hypoglycemia, maintenance dosage of the fixed combination of
metformin hydrochloride and glyburide in geriatric, debilitated, or malnourished patients
should not be titrated to the maximum dosage recommended for other patients.234
Combination Therapy with Metformin and a Thiazolidinedione
The manufacturers of pioglitazone or rosiglitazone state that combination therapy with
metformin hydrochloride may be used in patients who do not respond adequately to
either antidiabetic agent alone despite appropriate antidiabetic monotherapy, diet, and
exercise.237, 250 In patients with inadequate glycemic control receiving metformin
hydrochloride, the current dosage of metformin hydrochloride may be continued upon
initiation of thiazolidinedione therapy, as dosage adjustments of metformin
hydrochloride because of hypoglycemia are not likely to be needed.237, 250
The commercially available fixed-combination preparation containing metformin
hydrochloride and rosiglitazone is used as second-line therapy in patients who have
inadeqate glycemic control with metformin monotherapy.247 Metformin in fixed
combination with rosiglitazone also is used in patients with type 2 diabetes mellitus who
are already receiving each drug component separately. 247 Any change in the therapy
of type 2 diabetic patients should be undertaken with caution and appropriate
monitoring. 247
When the commercially available preparation containing metformin hydrochloride in
fixed combination with rosiglitazone is used as second-line therapy in patients
inadequately controlled on metformin or rosiglitazone monotherapy or to replace
concurrent therapy with the drugs given as separate tablets, dosage of the fixed
combination is based on the patient's current dosages of metformin hydrochloride
and/or rosiglitazone.247 In patients inadequately controlled on rosiglitazone
monotherapy, the usual initial dosage of metformin hydrochloride (in fixed combination
with rosiglitazone) is 1 g daily plus the patient's existing dosage of rosiglitazone, given in
2 divided doses. 247 In patients inadequately controlled with metformin hydrochloride
monotherapy, the usual initial dosage of rosiglitazone (in fixed combination with
metformin hydrochloride) is 4 mg daily plus the patient's existing dosage of metformin
hydrochloride, given in 2 divided doses. 247 The tablet strength of the fixed combination
that is selected should be the one that most closely provides the patient's existing
dosage of metformin hydrochloride or rosiglitazone, respectively. 247 (See Table.)
Initial Dosage of the Fixed Combination of Rosiglitazone and Metformin Hydrochloride (Avandamet)
Prior Therapy
Usual Initial Dosage of Avandamet
with meals.1 Concurrent insulin dosage should initially remain unchanged.1 Patients
should be monitored closely (e.g., with determination of fasting glucose concentrations)
during the dosage titration.1 When fasting plasma glucose concentrations decrease to
less than 120 mg/dL in patients receiving combined metformin and insulin therapy, the
insulin dosage may be decreased by 10-25%.1 Further dosage adjustments should be
individualized based on glycemic response.1 Periodic adjustments in dosage may be
necessary during continued combination therapy, as guided by monitoring of fasting
glucose and/or glycosylated hemoglobin concentrations.1
Dosage in Renal and Hepatic Impairment
Because of the risk of lactic acidosis, which often is fatal, metformin should not be used
in patients with renal disease or dysfunction and should be avoided in those with clinical
or laboratory evidence of hepatic disease.1 , 165, 243, 245, 246 (See Cautions: Lactic
Acidosis.)
Cautions
Adverse effects, principally GI effects, reportedly occur in about 5-50% of patients
receiving metformin therapy as conventional tablets in clinical trials and generally
required discontinuance of the drug in 6% or less of patients.1 , 6 , 18, 20, 23, 27, 134, 243,
245 246
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When metformin in used in fixed combination with glyburide, glipizide, or
rosiglitazone, the cautions, precautions, and contraindications associated with these
concomitant agents must be considered in addition to those associated with
metformin. 234, 247, 254
GI Effects
Adverse GI effects such as diarrhea1 , 31, 48, 49, 53, 78, 109, 118, 122, 135, 234, 243, 245,
246 254
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, nausea1 , 31, 53, 78, 109, 118, 122, 254, vomiting, 1 , 118, 122, 234, 243, 245, 246,
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flatulence,1 , 243, 245, 246 indigestion,1 , 243, 245, 246 and abdominal discomfort (e.g.,
bloating, abdominal cramping or pain),1 , 31, 35, 42, 53, 118, 122, 234, 243, 245, 246 are the
most common adverse effects associated with metformin-containing therapy as
conventional tablets;1 , 2 , 18, 20, 234, 243, 245, 246, 247, 254 diarrhea or nausea/vomiting
are the most common adverse effects reported in clinical trials with the
extended-release tablets.1 Because substantial diarrhea and/or vomiting may cause
dehydration and prerenal azotemia, metformin should be discontinued in patients who
develop such potentially serious GI effects; persistent diarrhea resolves promptly upon
discontinuance of the drug.1 , 18 Unpleasant or metallic taste (taste
disorder/disturbance),1 , 18, 118, 122, 243, 245, 246 which usually resolves spontaneously,
has been reported in approximately 1-5% of patients receiving metformin conventional
or extended-release tablets.1 , 2 , 3 , 30 Other adverse GI effects reported in 1-5% of
patients receiving conventional or extended-release metformin tablets include abnormal
stools,1 , 243, 245, 246 distended abdomen,1 constipation, 49, 118 or
dyspepsia/heartburn.1 , 49, 118 Anorexia also has been reported with metformin
therapy.3 , 6 , 18
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Serum folic acid concentrations do not appear to decrease
substantially in patients receiving metformin therapy.1 , 70, 82 Megaloblastic anemia has
been reported rarely (e.g., approximately 5 case reports outside the US to date) in
patients receiving metformin,1 , 2 , 18, 114, 243, 245, 246 and no increased incidence of
neuropathy has been observed in patients receiving the drug.1 , 18, 114, 123 Hematologic
parameters (e.g., hemoglobin, serum vitamin B 12 concentrations) should be monitored
annually in patients receiving metformin, and any apparent abnormalities appropriately
investigated and managed.1 , 243, 245, 246 Some clinicians have suggested that periodic
supplementation with parenteral vitamin B12 be considered in patients receiving
metformin who are at high risk for developing subnormal vitamin B12 levels (e.g.,
alcoholics, patients with low calcium or vitamin B12 intake or absorption).82, 114, 122,
134 148
Dermatologic Reactions
The manufacturer states that incidence of rash or dermatitis in patients receiving
metformin monotherapy is similar to that with placebo, and that the incidence of these
dermatologic effects in patients receiving metformin concomitantly with a sulfonylurea
antidiabetic agent is similar to that in individuals receiving a sulfonylurea antidiabetic
agent alone.1 , 30
Lactic Acidosis
Accumulation of metformin may occur in patients with renal impairment, and such
accumulation rarely can result in lactic acidosis, a serious, potentially fatal metabolic
disease.1 , 6 , 18, 20, 27, 29, 30, 62, 89, 96, 158 However, the risk of developing lactic
acidosis is less with metformin than with phenformin (no longer commercially available
in the US).3 , 6 , 20, 23(See Chemistry and Stability: Chemistry.) Lactic acidosis also may
occur in association with a variety of pathophysiologic conditions, including diabetes
mellitus, and may occur whenever substantial tissue hypoperfusion and hypoxemia
exist.1 , 32, 53, 63, 64, 93, 96, 123, 146 Lactic acidosis is characterized by elevated blood
lactate concentrations (exceeding 45 mg/dL), decreased blood pH (less than 7.35),
electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate
ratio.1 , 30
When metformin has been implicated as the cause of lactic acidosis, plasma drug
concentrations exceeding 5 mcg/mL generally have been observed.1 However, plasma
metformin concentrations may not be an accurate indication of tissue accumulation of
the drug in patients with metformin-induced lactic acidosis, and increased plasma
concentrations of lactic acid or lactic acidosis have been demonstrated during metformin
therapy despite normal plasma concentrations of the drug. 51, 64, 96, 146, 158 Patients
with lactic acidosis and normal plasma metformin concentrations also may have other
hydrochloride, GI symptoms, which are common during initiation of therapy, are unlikely
to be drug related; later occurrence of GI symptoms could be manifestations of lactic
acidosis or other serious disease.1 In diabetic patients, lactic acidosis may be
manifested as metabolic acidosis without ketoacidosis (ketonuria and ketonemia).1
Lactic acidosis constitutes a medical emergency requiring immediate hospitalization and
treatment;1 in such cases, metformin should be discontinued and general supportive
therapy (e.g., volume expansion, diuresis) should be initiated immediately.1 , 32, 62, 119
(See Acute Toxicity.)
Other Adverse Effects
Headache,118 agitation,118 dizziness,118 and tiredness118 were reported in a small
comparative study in geriatric diabetic patients receiving metformin.30, 85 Headache has
been reported in 9.3 or 8.9% of patients receiving metformin or metformin in fixed
combination with glyburide, respectively. 234 Headache has been reported in 5.3 or
12.6% of patients receiving metformin or metformin in fixed combination with glipizide,
respectively. 254 Dizziness has been reported in 3.8 or 5.5% of patients receiving
metformin or metformin in fixed combination with glyburide, respectively. 234 Dizziness
has been reported in 3.8 or 5.5% of patients receiving metformin or metformin in fixed
combination with glyburide, respectively. 234
Pneumonitis with vasculitis has been reported rarely with concomitant metformin and
oral sulfonylurea (e.g., glyburide) therapy.18, 74 Upper respiratory tract infection was
reported in 16.3 or 17.3% of patients receiving metformin or metformin in fixed
combination with glyburide, respectively. 234 Upper respiratory tract infection was
reported in 8.5 or 8.1-9.9% of patients receiving metformin or metformin in fixed
combination with glipizide, respectively, as initial therapy for type 2 diabetes mellitus.
254
Upper respiratory tract infection was reported in 10.7 or 10.3% of patients receiving
metformin or metformin in fixed combination with glipizide, respectively, as second-line
therapy for type 2 diabetes mellitus. 254 Urinary tract infection has been reported in 8 or
1.1% of patients receiving metformin alone or in fixed combination with glipizide,
respectively. 254 Hypertension has been reported in 5.6 or 2.9-3.5% of patients
receiving metformin alone or in fixed combination with glipizide, respectively. 254
Musculoskeletal pain has been reported in 6.7 or 8% of patients receiving metformin
alone or in fixed combination with glipizide, respectively. 254 Severe acute hepatitis
associated with marked elevations in serum hepatic aminotransferase values and
cholestasis has been reported following initiation of metformin therapy in a patient
receiving glipizide and enalapril.213
Precautions and Contraindications
When metformin in used in fixed combination with glyburide, the cautions, precautions,
and contraindications associated with glyburide must be considered in addition to those
associated with metformin.234
The diagnostic and therapeutic measures for managing diabetes mellitus that are
necessary to ensure optimum control of the disease with insulin are generally necessary
with metformin.12, 13, 14, 25, 26, 134, 179, 181 Clinicians who prescribe metformin should
be familiar with the indications, limitations, and patient-selection criteria for therapy with
oral antidiabetic agents to ensure appropriate patient management.10, 23, 30, 134, 187
Patients receiving metformin should be monitored with regular laboratory evaluations,
including blood glucose determinations, to determine the minimum effective dosage of
metformin hydrochloride when used either as monotherapy or in combination with a
sulfonylurea antidiabetic agent.1 , 2 , 14, 88, 179, 187 Glycosylated hemoglobin
(hemoglobin A1c [HbA1c ]) measurements also are useful, particularly for monitoring
long-term control of blood glucose concentration.1 , 2 , 134 Blood glucose determinations
are important to detect primary failure (inadequate lowering of blood glucose
concentration at the maximum recommended dosage) or secondary failure (loss of
control of blood glucose concentration following an initial period of effectiveness) to the
drug.1
Patients should be informed of the risks of lactic acidosis and conditions that predispose
to its development.1 (See Cautions: Lactic Acidosis.) Since metformin is excreted
substantially by the kidneys, accumulation of the drug resulting in lactic acidosis may
occur in patients with renal impairment;1 , 91, 93, 164 the risk of lactic acidosis increases
with degree of renal impairment.1 Therefore, the manufacturer states that renal function
should be evaluated prior to initiation of therapy with metformin preparations and at
least annually thereafter.1 , 2 , 77, 85, 234 The manufacturer also states that patients
whose serum creatinine concentrations exceed the upper limit of normal for their age
should not receive metformin.1 In patients in whom development of impaired renal
function is anticipated (e.g., those with blood glucose concentrations exceeding 300
mg/dL, who may develop renal dysfunction as a result of polyuria and volume
depletion),156 renal function should be monitored more frequently; the drug should be
discontinued if evidence of renal impairment is present.1 , 2 , 156, 164 In addition, drugs
that may affect renal function, produce substantial hemodynamic changes, or interfere
with metformin elimination (e.g., cimetidine) should be used with caution in patients
receiving metformin.1 , 134 Hemodialysis has been used in patients with lactic acidosis to
accelerate the clearance of metformin. (See Acute Toxicity.)
Metformin should not be used in patients with congestive heart failure requiring drug
therapy (e.g., digoxin, furosemide), such as those with unstable or acute congestive
heart failure. 1 , 209, 214, 215 These patients are at risk for hypoperfusion and hypoxemia,
which may lead to lactic acidosis.1 , 215 Some clinicians suggest that metformin may be
reinstituted once acute heart failure has resolved and renal function is normal (as
measured by creatinine clearance).215
Since administration of parenteral iodinated contrast media may lead to acute alteration
of renal function and has been associated with lactic acidosis in patients receiving
metformin, the manufacturer states that metformin should be discontinued at the time of
or prior to the procedure, and should not be reinstituted until 48 hours after such
procedures;1 , 234, 243, 245, 246, 247, 254 metformin should not be reinstituted until renal
function has been evaluated and found to be normal.1 , 234, 247 Metformin also should
be discontinued temporarily in patients undergoing surgery, except minor surgery that is
not associated with restricted food or fluid intake; the drug should be reinitiated only
when patient's oral intake has resumed and renal function has been shown to be
normal.1 , 254 In addition, any diabetic patient previously well controlled with metformin
therapy who develops a clinical illness (especially one that is vague and poorly defined)
or whose laboratory test results deviate from normal should be evaluated promptly for
evidence of ketoacidosis or lactic acidosis.1 , 88, 169 (See Cautions: Lactic Acidosis.)
Such evaluation should include determinations of serum electrolytes and ketones, blood
glucose, and if indicated, blood pH, lactate, pyruvate, and metformin concentrations.1 ,
88 134 156 169
,
,
,
Since cardiovascular collapse (shock), congestive heart failure,
ischemic heart disease (e.g., acute myocardial infarction), peripheral vascular disease
(e.g., claudication), obstructive airways disease, or other conditions that are likely to
cause central hypoxemia or reduced peripheral perfusion have been associated with
lactic acidosis and prerenal azotemia, metformin should be discontinued in patients
developing such conditions.1 , 18, 20, 30, 62, 76, 91, 93, 146, 156, 158, 254
The cardiovascular risks associated with use of oral antidiabetic agents have not been
fully determined.1 , 2 , 34, 136, 216 In 1970, the University Group Diabetes Program
(UGDP) reported that administration of oral antidiabetic agents (i.e., tolbutamide or
phenformin) was associated with increased cardiovascular mortality compared with
treatment with dietary regulation alone or with dietary regulation and insulin.1 , 191, 192,
200 234
,
The UGDP reported that type 2 diabetic patients who were treated for 5-8 years
with dietary regulation and a fixed dose (1.5 g daily) of tolbutamide or dietary regulation
and a fixed dose (100 mg daily) of phenformin (currently not commercially available in
the US) had a cardiovascular mortality rate approximately 2.5 times that of patients
treated with dietary regulation alone.1 , 191, 192, 200, 234 Although a substantial increase
in total mortality was observed only with phenformin, both tolbutamide and phenformin
were discontinued because of the increases in cardiovascular mortality.1 , 191, 192, 200,
234
The results of the UGDP study have been analyzed exhaustively, and there has
been general disagreement in the scientific and medical communities regarding the
study's validity and clinical importance. 1 , 10, 23, 180, 198, 200 The management of
patients with type 2 diabetes mellitus has changed substantially since the UGDP was
initiated in 1961.10, 180, 184, 198 Dietary management, weight reduction, better control
of blood glucose concentration, and regular physical activity have received greater
emphasis in the management of diabetes in these patients.8 , 10, 14, 24, 25, 26, 88, 179,
181
In addition, reduction of existing cardiovascular risk factors (e.g., management of
hypertension, discontinuance of smoking) has been emphasized.10, 14, 26, 88, 179, 181,
185 187
,
The American Diabetes Association (ADA) currently recommends that clinician
judgment in the management of type 2 diabetes mellitus be based on assessment of all
available therapeutic information, including data on cardiovascular risk factors, the
positive effect of metabolic control of diabetes on cardiovascular disease, the
importance of dietary management and weight reduction in obese diabetic patients, the
importance of regular physical activity, and objective reports in the scientific literature
that pertain to the UGDP study and to the long-term use of sulfonylureas. 10, 14, 26, 136
contraindicated in patients with congestive heart failure requiring drug therapy.1 , 234,
247 254
,
Metformin-containing therapy also is contraindicated as sole therapy in patients
with type 1 diabetes and in patients with diabetes complicated by acute or chronic
metabolic acidosis, including diabetic ketoacidosis with or without coma.1 , 2 , 234, 247
Metformin alone or in fixed combination with glyburide, glipizide, or rosiglitazone also is
contraindicated in patients with known hypersensitivity any ingredient in the respective
formulations.
Pediatric Precautions
Safety and efficacy of metformin conventional or extended-release tablets in children
younger than 10 or younger than 17 years of age, respectively, have not been
established.1 , 3 , 4 , 30, 134, 243, 245, 246 Data from a placebo-controlled clinical trial
indicated a similar glycemic response and adverse effect profile in pediatric patients
(10-16 years of age) as in adults.1 , 246 (See Diabetes Mellitus: Metformin Monotherapy,
in Uses.) The safety and efficacy of metformin in fixed combination with glyburide,
glipizide, or rosiglitazone in pediatric patients have not been established. 234, 247, 254
The American Diabetes Association (ADA) states that most pediatric diabetologists use
oral antidiabetic agents in children with type 2 diabetes mellitus because of greater
patient compliance and convenience for the patient's family and a lack of evidence
demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.235
Geriatric Precautions
It is not known whether geriatric patients respond differently to metformin than younger
patients.1 Data from controlled clinical trials with metformin in fixed combination with
glyburide or glipizide have not revealed age-related differences in safety and efficacy of
the combination, but greater sensitivity of geriatric patients to these fixed combinations
cannot be ruled out. 234, 254 Since metformin is excreted principally by the kidneys and
renal function declines with age, the drug should be used with caution in geriatric
patients.1 , 3 , 4 , 30, 85, 174 234, 247, 254 Metformin therapy should be used only in
patients with normal renal function. 1 , 234, 254 As geriatric patients are at risk for the
development of lactic acidosis, metformin therapy should not be initiated in geriatric
patients 80 years of age and older without confirmation of adequate renal function as
measured by creatinine clearance.209, 214, 234, 247, 254 In addition, renal function
should be monitored periodically and care should be taken in dosage selection for
geriatric patients; such patients generally should not receive the maximum
recommended dosage of metformin hydrochloride.1 , 2 , 3 , 4 , 30, 85, 174, 234, 247, 254
Mutagenicity and Carcinogenicity
No evidence of mutagenicity or chromosomal damage was observed in vivo in a
micronucleus test in mice or in in vitro test systems, including microbial (Ames test) and
mammalian (mouse lymphoma and human lymphocytes) assays.1
No evidence of carcinogenic potential was seen in a 104-week study in male and female
rats receiving metformin hydrochloride dosages up to and including 900 mg/kg daily or
in a 91-week study in male and female mice receiving metformin hydrochloride at
dosages up to and including 1500 mg/kg daily; these dosages are about 3 times the
maximum recommended human daily dosage based on body surface area.1 However,
an increased incidence of benign stromal uterine polyps was observed in female rats
treated with 900 mg/kg of metformin hydrochloride daily.1
Pregnancy, Fertitlity and Lactation
Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600
mg/kg daily (about twice the maximum recommended human daily dosage based on
body surface area or about 2 and 6 times the maximum recommended human daily
dosage of extended-release tablets [2 g] based on body surface area comparisons with
rats and rabbits, respectively)1 have not revealed evidence of harm to the fetus.1
Determination of fetal concentrations of metformin suggest that a partial placental
barrier to the drug exists. 1 , 3 Since abnormal maternal blood glucose concentrations
during pregnancy may be associated with a higher incidence of congenital
abnormalities, 1 , 115 most experts recommend that insulin be used during pregnancy to
maintain optimum control of blood glucose concentration.1 , 3 , 4 , 18, 72, 88, 92
There are no adequate and controlled studies to date using metformin in pregnant
women.1 Limited data from uncontrolled or retrospective studies are conflicting with
regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3
g daily) on neonatal morbidity (e.g., congenital malformations) and mortality. 92, 115
Metformin should be used during pregnancy only when clearly needed.1 , 3 , 4
No evidence of impaired fertility was observed in rats following administration of
metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum
recommended human dosage based on body surface area).1
Metformin is distributed into milk of lactating rats and achieves concentrations
comparable to those attained in plasma.1 , 85 Since it is not known if metformin is
distributed into milk in humans, a decision should be made whether to discontinue
nursing or the drug, taking into account the importance of the drug to the woman. 1 , 3 , 4
If metformin is discontinued in a nursing mother and dietary therapy is inadequate for
glycemic control, insulin therapy should be considered.1
Drug Interactions
Antidiabetic Agents
Although hypoglycemia occurs infrequently in patients receiving metformin therapy
alone,1 , 19, 62, 78, 166 hypoglycemia may occur when the drug is used concomitantly
with a sulfonylurea antidiabetic agent (e.g., glyburide) and/or insulin.1 , 15, 78, 94, 99 (See
Cautions: Precautions and Contraindications.)
In a single-dose study in patients with type 2 diabetes mellitus, concomitant
administration of glyburide with metformin did not alter the pharmacokinetics or
pharmacodynamics of metformin.1 Although variable decreases in the area under the
blood concentration-time curve (AUC) and peak blood concentration of glyburide were
observed, the single-dose nature of this study and the lack of a relationship between
glyburide blood concentrations and pharmacodynamic effects preclude evaluation of the
clinical importance of these effects.1
In a single-dose study, administration of metformin concomitantly with an a-glucosidase
inhibitor (acarbose) resulted in an acute decrease in the bioavailability of metformin.138,
201
Coadministration of guar gum (10 g) and metformin hydrochloride (1.7 g) with a
standard meal in healthy individuals reduced and delayed the absorption of metformin
from the GI tract.18, 85, 99, 106
Diuretics
Thiazide diuretics can exacerbate diabetes mellitus, resulting in increased requirements
of oral antidiabetic agents, temporary loss of diabetic control, or secondary failure to the
antidiabetic agent.1 , 91, 139, 143, 151, 152, 153, 154, 159, 160 If control of diabetes is
impaired by a thiazide diuretic, clinicians may consider substituting a less diabetogenic
diuretic (e.g., potassium-sparing diuretic), reducing the dosage of or discontinuing the
diuretic, or increasing the dosage of the oral antidiabetic agent.73, 134, 152, 153, 154, 159,
160
transport sites. 1 , 75 The manufacturer states that the possibility of other cationic drugs
that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine,
procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin) decreasing the
urinary excretion of metformin should be considered.1 , 30 Patients receiving metformin
concomitantly with a cationic drug that is excreted by the proximal renal tubules should
be monitored carefully and the need for possible dosage adjustment of either agent
considered.1
-Adrenergic Blocking Agents
In single-dose studies in healthy individuals, concomitant administration of metformin
and propranolol did not alter the pharmacokinetics of either drug.1 However, several
potential interactions between -adrenergic blocking agents and oral antidiabetic agents
(e.g., sulfonylureas, metformin) exist.91, 127, 143, 153, 159, 160, 198 -Adrenergic
blocking agents may impair glucose tolerance;73, 143, 152, 153, 159 increase the
frequency or severity of hypoglycemia;127 block hypoglycemia-induced tachycardia but
not hypoglycemic sweating, which may actually be increased;91, 153, 159 delay the rate
of recovery of blood glucose concentration following drug-induced hypoglycemia;91, 127,
153
alter the hemodynamic response to hypoglycemia, possibly resulting in an
exaggerated hypertensive response;153 and possibly impair peripheral circulation.153
Nonselective - adrenergic blocking agents (e.g., propranolol, nadolol) without intrinsic
sympathomimetic activity are more likely to affect glucose metabolism than more
selective -adrenergic blocking agents (e.g., metoprolol, atenolol) or those with intrinsic
sympathomimetic activity (e.g., acebutolol, pindolol).36, 73, 91, 143, 152, 159, 160, 173
Signs of hypoglycemia (e.g., tachycardia, blood pressure changes, tremor, feelings of
anxiety) mediated by catecholamines may be masked by either nonselective or
selective -adrenergic blocking agents.128, 143, 153, 159 These drugs should be used
with caution in patients with type 2 diabetes mellitus who are receiving antidiabetic
agents, especially in those with labile disease or in those prone to hypoglycemia.36, 83,
91 127 128 153
,
,
,
Use of low-dose, selective 1 -adrenergic blockers (e.g., metoprolol) or
-adrenergic blocking agents with intrinsic sympathomimetic activity in patients
receiving oral antidiabetic agents may theoretically decrease the risk of affecting
glycemic control.36, 143, 152, 160, 173 When an oral antidiabetic agent and a
-adrenergic blocking agent are used concomitantly, the patient should be advised
about and monitored closely for altered antidiabetic response.134
Alcohol
Combined use of alcohol and metformin can increase the risk of hypoglycemia and
lactic acidosis, since alcohol decreases lactate clearance and hepatic gluconeogenesis
and may increase insulin secretion.1 , 2 , 18, 33, 63, 72, 76, 91, 93, 107, 143 (See Cautions:
Lactic Acidosis.) Excessive alcohol intake, on an acute or chronic basis, should be
avoided in patients receiving metformin therapy.1
Protein-Bound Drugs
Binding of metformin to plasma proteins is negligible; therefore, metformin is less likely
to interact with drugs that are highly protein bound compared with sulfonylurea
Pharmacology
Antidiabetic Effects
Metformin hydrochloride, a biguanide antidiabetic agent, is chemically and
pharmacologically unrelated to sulfonylurea antidiabetic agents.1 , 2 , 18, 20, 27, 28, 29
Unlike sulfonylureas, biguanides such as metformin lower blood glucose concentrations
in patients with type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) without
increasing insulin secretion from pancreatic cells;1 , 2 , 3 , 4 , 18, 20, 27, 31, 40, 60, 134
however, metformin is ineffective in the absence of some endogenous or exogenous
insulin.18, 27, 40, 71, 122 Biguanides usually do not produce hypoglycemia in diabetic
patients and do not affect normal blood glucose concentrations in nondiabetic
individuals; metformin, even in excessive dosage, normally does not lower glucose
concentrations below euglycemia.1 , 2 , 18, 20, 27, 28, 29, 72, 102, 103, 111 (See Acute
Toxicity.) Therefore, while biguanides as well as sulfonylureas historically have been
referred to as oral hypoglycemic agents,27, 28, 29 biguanides such as metformin are
more appropriately referred to as antihyperglycemic agents.1 , 6 , 18, 20, 157
Type 2 diabetes mellitus is characterized by insulin resistance (impaired uptake and
disposal of glucose by peripheral tissues and excessive glucose production by the liver),
and abnormal insulin secretion, which may result in insulin deficiency (impaired
secretion of insulin from pancreatic cells) during the late stage of the disease.8 , 18, 20,
24 25 27 28 31 40 41 42 44 71 81 134 145 146 161
, , , , , , , , , , ,
,
,
,
(See Uses.) Although the
underlying pathophysiology of type 2 diabetes mellitus may be similar in obese and
nonobese patients with the disease, severe peripheral and hepatic insulin resistance
appears to predominate in obese patients, while nonobese patients tend to have milder
degrees of insulin resistance but more marked insulin deficiency; however, both
abnormalities eventually occur in the course of the disease.8 , 9 , 18, 60, 134, 145, 178
Obesity itself often is associated with insulin resistance and an elevated rate of fatty
acid oxidation, which may contribute to the glucose intolerance observed in obese
patients with type 2 diabetes mellitus.9 , 11, 27, 59, 73, 134, 146, 178, 179
Metformin lowers both basal (fasting) and postprandial glucose concentrations in
patients with type 2 diabetes mellitus.1 , 2 , 18, 22 Although the precise mechanism(s) by
which metformin exerts its antihyperglycemic effect has not been fully established,
current evidence suggests that the drug improves both peripheral and hepatic sensitivity
to insulin.18, 31, 33, 40, 41, 42, 44, 52, 58, 60, 81, 146 Improved insulin sensitivity occurs
principally as a result of decreased hepatic glucose production and enhanced
insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal
muscle, adipocytes);18, 31, 40, 41, 42, 44, 60, 81, 146, 149 the relative contribution of these
mechanisms to the antihyperglycemic effect of metformin has not been fully
elucidated.18, 42, 44, 71, 72, 135, 146, 161 Increases of 18-29% in the rate of
insulin-stimulated glucose uptake (principally by skeletal muscle) have been reported in
patients with type 2 diabetes mellitus with metformin hydrochloride and in
normoglycemic insulin-resistant individuals in whom glucose utilization during therapy
(0.5-3 g daily) generally was evaluated using a euglycemic, hyperinsulinemic clamp
demonstrated improved insulin binding with metformin.18, 54, 67, 84, 98, 145 However,
conflicting data also have been reported,40, 41, 42, 79, 84 and a direct correlation
between increases in insulin binding and decreases in blood glucose concentration has
not been observed.18, 20, 22, 37, 40, 41, 42, 71, 134 In in vitro studies in animal and
human skeletal muscle cells or adipocytes, metformin has increased glucose uptake
through enhancement of insulin-stimulated recruitment of specific glucose transporters
(e.g., GLUT-1, GLUT-4) to the plasma membrane of insulin target cells (e.g., adipose
tissue, skeletal muscle) and through increases in the activity of these glucose
transporters.4 , 33, 40, 47, 52 In in vitro studies using metformin concentrations within the
therapeutic range, metformin has not consistently enhanced basal glucose uptake,
which is noninsulin-mediated; however, in vitro data may not accurately reflect in vivo
actions of the drug, and further study is needed to determine whether metformin acts
through insulin-dependent or -independent pathways, or both, to affect basal glucose
uptake.37, 40, 47, 52, 134, 149, 150
Metformin accumulates in the walls of the intestine but does not appear to have
clinically important effects on glucose absorption.6 , 18, 28, 37, 44, 134, 146
Antilipemic Effects
Metformin has demonstrated modest favorable effects on serum lipids, which are often
abnormal in patients with type 2 diabetes mellitus.1 , 3 , 6 , 15, 18, 20, 34, 146 In clinical
studies, particularly in patients with elevated baseline serum lipid concentrations (e.g.,
patients with type II, type III, or type IV hyperlipoproteinemia), metformin alone or
combined with a sulfonylurea antidiabetic agent lowered fasting serum triglyceride
concentrations and total and LDL-cholesterol concentrations without adversely affecting
other serum lipids.1 , 3 , 4 , 6 , 15, 18, 20, 31, 34, 42, 46, 53, 58, 78, 81, 102, 135, 146 Modest
reductions (e.g., 10-20%) in serum triglyceride concentrations noted with metformin
therapy generally have been attributed to decreased hepatic synthesis of
VLDL-cholesterol, particularly in patients with elevated baseline triglyceride
concentrations.1 , 3 , 4 , 6 , 18, 20, 22, 31, 35, 42, 102, 146 Characteristics of patients who
are likely to exhibit a decrease in serum triglycerides with metformin therapy have not
been determined, and correlation of potential antilipemic effect with the degree of
glycemic control has been inconsistent.46, 49, 72, 78 Small reductions (e.g., 5-10%) in
serum total cholesterol also have been reported in some studies;15, 20, 31, 42, 46, 58, 78,
102
these effects may be attributed to decreased LDL- or VLDL-cholesterol
concentrations.6 , 15, 18, 31, 42, 46, 58, 78, 102 Increases in HDL-cholesterol also have
been reported with metformin therapy in nondiabetic patients18, 20 and in those with
type 2 diabetes mellitus.18, 31, 42, 102 Consistent changes in plasma glycerol and free
fatty acid concentrations have not been reported during metformin therapy in patients
with NIDDM or in nondiabetic individuals.20, 31, 35, 42, 44, 58, 61, 68, 81, 102, 135 A
reduction in free fatty oxidation has been suggested as a possible mechanism for the
decrease in plasma free fatty acids observed in some studies with metformin therapy.31,
35 42 68 102
, , ,
Hematologic Effects
Metformin may exert potentially beneficial effects on the fibrinolytic system by increasing
the activity of tissue-type plasminogen activator (t-PA) and/or reducing concentrations of
plasminogen activator inhibitor-1 (PAI-1) in nondiabetic, hypertensive patients and in
patients with type 2 diabetes mellitus; serum fibrinogen concentrations do not appear to
be affected by metformin therapy.18, 34, 55, 56, 58, 108, 109, 136 Patients with type 2
diabetes mellitus, hypertension, and obesity often have hyperinsulinemia and a high
incidence of vascular disease.55, 108 PAI-1 concentrations, which are regulated by
insulin, may be substantially increased in patients with type 2 diabetes mellitus and in
obese individuals,34, 55, 108, 136 and it has been suggested that the reduced fibrinolytic
activity associated with elevated PAI-1 concentrations may be important in the
pathogenesis of vascular disease in these individuals.34, 55, 108, 134, 136 Metformin has
been shown to increase fibrinolytic activity (as measured by blood clot lysis time,
euglobulin fibrinolytic activity, and by increases in t-PA activity) in patients with coronary
artery disease, obese individuals, and in patients with mild hypertension; increases in
fibrinolytic activity with metformin therapy generally occur in patients who have low
fibrinolytic activity at baseline.56, 58, 108 Reduced platelet density, activation, and/or
aggregation; 18, 73, 109 decreased blood pressure; and decreased peripheral arterial
resistance18, 57, 58 also have been reported in some normotensive patients with type 2
diabetes mellitus and in nondiabetic, mildly hypertensive patients receiving metformin;
however, whether these effects are associated with the drug or are secondary to
improvement in glycemic control or a reduction in body weight has not been
determined.18, 57, 58, 73, 109, 146
Other Effects
Therapy with metformin may be associated with weight stabilization19, 35, 41, 42, 46, 69
or loss.15, 31, 17, 45, 49, 57, 78, 81, 84, 118 Although the exact mechanism associated
with such alterations in weight has not been established,6 , 16, 17, 20, 30, 31, 81, 85
suggested mechanisms include the absence of a hyperinsulinemic effect (which if
present may increase appetite and/or lipogenesis)15, 17, 18, 72 and decreased dietary
intake associated with adverse GI effects of metformin. 17, 29, 85, 189 The
antihyperglycemic effect of the drug does not appear to be related to weight loss in
patients with type 2 diabetes mellitus receiving metformin, nor does weight loss appear
to be dose related.6 , 17, 20, 34 Limited data from studies comparing metformin therapy
with oral sulfonylurea (e.g., glyburide, chlorpropamide, tolbutamide) therapy indicate
that patients with type 2 diabetes mellitus receiving oral sulfonylureas gained weight or
lost less weight than patients receiving metformin.15, 16, 17, 20, 46, 57, 118, 134
Metformin has little or no effect on fasting plasma glucagon, somatostatin, serum growth
hormone, or serum cortisol concentration in patients with normal renal function;
glucagon, growth hormone, and cortisol concentrations are elevated in patients with
lactic acidosis and renal failure who have been receiving metformin.6 , 61, 62, 81, 135
Pharmacokinetics
The pharmacokinetics of metformin in patients with normal renal function do not appear
24-48 hours and generally average about 1 mcg/mL or less. 1 , 30, 38, 51 A precise
correlation between plasma metformin concentrations and the drug's antihyperglycemic
effect has not been established.5 , 51, 53, 72 In addition, plasma metformin
concentrations generally have shown no correlation with plasma lactate concentrations
during metformin therapy in patients with type 2 diabetes mellitus.5 , 30, 53, 64, 96, 134
Although metformin-associated lactic acidosis generally has been associated with
plasma metformin concentrations exceeding 5 mcg/mL1 , 2 , 62, 96, 119 (see Cautions:
Lactic Acidosis), such high concentrations reportedly were not observed during
controlled clinical trials with the drug, even at maximum dosage (2.5-2.55 g daily).1 , 134
Satisfactory control of blood or plasma glucose concentration may occur within a few
days to 1 week following initiation of metformin therapy in patients with type 2 diabetes
mellitus, but the maximum antihyperglycemic effect may be delayed for up to 2
weeks.18, 53, 72, 98, 134 Following discontinuance of metformin therapy, blood glucose
concentration increases within 2 weeks.53, 134
Distribution
Metformin is distributed rapidly in animals and humans into peripheral body tissues and
fluids, particularly the GI tract; the drug also appears to distribute slowly into
erythrocytes and into a deep tissue compartment (probably GI tissues).30, 50, 65, 72, 89,
134 162 167
,
,
The highest tissue concentrations of metformin (at least 10 times the
plasma concentration) occur in the GI tract (e.g., esophagus, stomach, duodenum,
jejunum, ileum), with lower concentrations (twice the plasma concentration) occurring in
kidney, liver, and salivary gland tissue. 6 , 18, 44, 50, 51, 65, 72, 162 The drug distributes
into salivary glands with a half-life of about 9 hours.50, 65 Metformin concentrations in
saliva are tenfold lower than those in plasma and may be responsible for the metallic
taste reported in some patients receiving the drug.50, 65 Any local effect of metformin on
glucose absorption in the GI tract may be associated with the relatively high GI
concentrations of the drug compared with those in other tissues.6 , 18, 43 It is not known
whether metformin crosses the blood-brain barrier or the placenta in humans or if the
drug is distributed into human milk; however, in lactating rats, metformin is distributed
into breast milk at levels comparable to those in plasma.1 , 2 , 85
Following oral administration of single 850-mg doses of metformin hydrochloride as
conventional tablets, the apparent volume of distribution has been reported to average
654 L.1 Volume of distribution reported after IV administration of the drug generally has
been smaller (e.g., 63-276 L) than that with oral administration, perhaps because of less
drug binding in the GI tract and/or different methods of determining volume of
distribution in various studies.30, 50, 51, 89, 134 Unlike oral sulfonylurea antidiabetic
agents, which are more than 90% bound to plasma proteins, metformin is negligibly
bound to plasma proteins.1 , 18, 50, 51, 65, 85, 89 Metformin equilibrates freely between
erythrocytes and plasma, most likely as a function of time; drug bound to erythrocytes is
approximately 5% of total blood concentration.1 , 2 , 3 , 18, 89
Elimination
Stability
Commercially available metformin hydrochloride conventional (including
fixed-combination preparations with glipizide or rosiglitazone) and extended-release
tablets should be stored at a controlled room temperature of 20-25C and protected
from light but may be exposed to temperatures ranging from 15-30C .1 , 247, 254
Fixed-combination preparations containing metformin hydrochloride and glyburide
should be stored at a controlled room temperature up to 25C and be protected from
light.234
Preparations
Metformin Hydrochloride
Oral
Tablets, film-
500 mg
coated
Bristol-Myers Squibb
850 mg
Glucophage , (with
povidone) Bristol-Myers Squibb
1g
Glucophage , (with
povidone) Bristol-Myers Squibb
Glucovance, Bristol-Myers
Glucovance , Bristol-Myers
, mg
GlaxoSmithKline
500 mg with Rosiglitazone 2 Avandamet
, mg
GlaxoSmithKline
500 mg with Rosiglitazone 4 Avandamet
, mg
GlaxoSmithKline
References
1. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and
Glucophage XR (metformin hydrochloride) extended-release tablets prescribing