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Metformin: An Update
Dmitri Kirpichnikov, MD; Samy I. McFarlane, MD; and James R. Sowers, MD

Metformin is an insulin-sensitizing agent with potent antihyper-
Although the precise mechanism of hypoglycemic action of met-
glycemic properties. Its efficacy in reducing hyperglycemia in
formin remains unclear, it probably interrupts mitochondrial oxi-
type 2 diabetes mellitus is similar to that of sulfonylureas, thia-
dative processes in the liver and corrects abnormalities of intra-
zolidinediones, and insulin. Metformin-based combination therapy
cellular calcium metabolism in insulin-sensitive tissues (liver,
is often superior to therapy with a single hypoglycemic agent. The
skeletal muscle, and adipocytes) and cardiovascular tissue.
antihyperglycemic properties of metformin are mainly attributed to
suppressed hepatic glucose production, especially hepatic glu-

Ann Intern Med. 2002;137:25-33.
coneogenesis, and increased peripheral tissue insulin sensitivity.
For author affiliations, see end of text.
Insulin resistance contributes greatly to development of arytoweightlossorfatredistribution)mayhaveadditional
cardiovascular disease in patients with the metabolic syn- cardiovascular benefits in insulin-resistant persons treated drome and its extreme presentation, type 2 diabetes melli- with metformin (13, 14). Weight loss during metformin tus. Therefore, treatment with an insulin-sensitizing agent, treatment has been attributed to decreased net caloric in- such as metformin, in patients with type 2 diabetes melli- take (15), probably through appetite suppression, an effect tus may correct several of the primary pathophysiologic that is largely independent of gastrointestinal side effects of abnormalities of the metabolic syndrome. In diabetic pa- metformin (such as nausea and diarrhea) (10). Reduction tients, metformin appears to provide cardiovascular protec- in hyperinsulinemia related to reduced insulin resistance tion that cannot be attributed only to its antihyperglycemic may have an additive effect on weight reduction in obese effects. These additional cardioprotective effects in these insulin-resistant persons (13, 14).
patients may be related to the favorable actions of met- At doses of 500 to 1500 mg, metformin has an abso- formin on lipid metabolism, vascular smooth-muscle and lute oral bioavailability of 50% to 60% (16). The drug is cardiomyocyte intracellular calcium handling, endothelial not protein bound and therefore has a wide volume of function, hypercoagulation, and platelet hyperactivity. We distribution (8), with maximal accumulation in the small- discuss known mechanisms by which metformin exerts its intestine wall (17). Metformin undergoes no modifications beneficial glycemic and cardiovascular actions.
in the body and is secreted unchanged by rapid kidneyexcretion (through glomerular filtration and, possibly, tu- CLINICAL ROLE OF METFORMIN
bular secretion) (8). Impaired kidney function slows elim- Metformin, an insulin-sensitizing biguanide used to ination and may cause metformin accumulation (18). The treat type 2 diabetes, has been shown to be as effective as H2-blocker cimetidine competitively inhibits renal tubular insulin or sulfonylureas when used as monotherapy (1–5).
secretion of metformin, significantly decreasing its clear- In conjunction with diet, metformin reduces fasting glu- ance and increasing its bioavailability (16, 19).
cose concentration by 2.78 to 3.90 mmol/L (50 to 70mg/dL), which corresponds to a 1.3% to 2.0% reductionin hemoglobin A1c values (1, 2, 4, 6 – 8). The magnitude of METFORMIN AS A PART OF COMBINATION THERAPY
plasma glucose reduction is related to pretreatment glucose Metformin has been shown to be effective in combi- levels (7, 9). The efficacy of metformin monotherapy has nation with insulin, sulfonylureas (2, 10, 20, 21), and thia- been shown to be independent of age, body weight, eth- zolidinediones (22). This finding is important because nicity, duration of diabetes, and insulin and C-peptide lev-els (1, 2).
single-drug therapy often fails to maintain normoglycemia, Metformin may have special benefits in overweight particularly as diabetes progresses (23, 24). As seen in the patients with type 2 diabetes. Unlike sulfonylureas, insulin, United Kingdom Prospective Diabetes Study (UKPDS), and thiazolidinediones, metformin does not affect body 50% of patients treated with diet or a single antidiabetic mass index (1) or decreases body weight in obese patients drug achieved the target hemoglobin A1c value of less than with (4, 10) and without (11, 12) diabetes. Significant 7% after 3 years of follow-up; after 9 years, only 25% reductions in total body fat and visceral fat have been ob- maintained this goal (24). As diabetes progresses and treat- served in women with preexistent abdominal or visceral ment with maximal doses of sulfonylurea fails, addition of obesity who are treated with metformin (11). Excessive fat metformin significantly improves glycemic control (2). In localized to the paraintestinal region is a major contributor the UKPDS trial, combination therapy tended to control to the pathogenesis of the cardiovascular metabolic syn- glycemia more effectively than monotherapy (hemoglobin drome (13, 14), and the reduction in visceral fat (second- A1c value, 0.075 [7.5%] versus 0.081 [8.1%]) (23).
2002 American College of Physicians–American Society of Internal Medicine E-25
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Update Metformin: An Update PRACTICAL CONSIDERATIONS IN METFORMIN THERAPY
feres with mucosal-cell intracellular calcium handling, thus The ideal patient for initiation of metformin treatment disrupting calcium-dependent absorption of vitamin B12 in would be an obese person with type 2 diabetes mellitus who the ileum (30). Such decreases in vitamin B12 levels rarely has normal kidney function (creatinine concentration ⬍133 have clinical significance (2, 9).
␮m d/L [⬍1.5 mg/dL] in men and ⬍124 ␮m d/L in women, Development of hypoglycemia during metformin or creatinine clearance ⬎1.17 mL/s without coexistent symp- monotherapy is rare because metformin only partially sup- tomatic congestive heart failure or a hypoxic respiratory con- presses gluconeogenesis in the liver and does not stimulate dition) (9, 16, 25). Contraindications to metformin therapy insulin production (9, 31).
are liver failure, alcoholism, and active moderate to severe in- Lactic acidosis is a life-threatening complication of bigua- fection (9, 25); these conditions predispose to development of nide therapy that carries a mortality rate of 30% to 50% (28).
lactic acidosis, either by increased production or decreased Metformin therapy may increase blood lactate levels (1) and is metabolism of lactic acid (9, 16 –18, 25). Administration of occasionally associated with development of lactic acidosis (2, radiocontrast material to a patient with diabetes may worsen 28). The estimated incidence of metformin-associated lactic already-compromised kidney function and cause accumula- acidosis is 0.03 cases per 1000 patient-years (25), which is 10 tion of metformin, leading to toxic levels of drug. Further- to 20 times lower than that seen with phenformin therapy more, administration of general anesthesia may cause hypo- (28). Development of lactic acidosis appears to be unrelated to tension, which leads to renal hypoperfusion and peripheral plasma metformin concentrations (28), and even in persons tissue hypoxia with subsequent lactate accumulation (25–28).
with chronic renal insufficiency, metformin accumulation Therefore, if administration of radiocontrast material is re- does not necessarily lead to lactic acidosis (18). Developmentof lactic acidosis is almost always related to coexistent hypoxic quired or urgent surgery is needed, metformin should be conditions that are probably responsible for the associated withheld and hydration maintained until preserved kidney high mortality rate. In one report, 91% of patients who de- function is documented at 24 and 48 hours after the interven- veloped lactic acidosis while being treated with metformin had tion (9, 26 –28). Metformin should be used with caution in a predisposing condition, such as congestive heart failure, re- elderly patients, whose reduced lean body mass may lead to nal insufficiency, chronic lung disease with hypoxia, or age misleading low creatinine concentrations that fail to reflect older than 80 years (26). Thus, patients with compromised decreased glomerular filtration rates (9, 25–28).
renal function or coexistent hypoxic conditions should not be Metformin therapy should be initiated with a single given metformin. Chronic or acute intake of large amounts of dose of medication (usually 500 mg) taken with the pa- alcohol may potentiate the effect of metformin on lactate me- tient's largest meal to prevent gastrointestinal symptoms.
tabolism. A careful history of alcohol use is therefore impor- Gastrointestinal symptoms generally disappear within 2 tant before starting metformin therapy (26, 27).
weeks of treatment (10, 11). Medication doses may beincreased by 500-mg increments every 1 to 2 weeks, asindicated by glycemic control, until a desirable blood glu- MECHANISMS OF ANTIHYPERGLYCEMIC ACTION OF
cose level or the maximal recommended daily metformin dose of 2550 mg is reached (2, 25). The hypoglycemic The glucose-lowering effects of metformin are mainly a effect of metformin is dose related, and a plateau of hypo- consequence of reduced hepatic glucose output (primarily glycemic action is achieved at a daily dose of 2000 mg (6).
through inhibition of gluconeogenesis and, to a lesser extent, Side effects of metformin are mostly limited to diges- glycogenolysis) and increased insulin-stimulated glucose up- tive tract symptoms, such as diarrhea, flatulence, and ab- take in skeletal muscle and adipocytes (25, 27, 31–35) (Figure
dominal discomfort (1, 6, 8 –10). These symptoms are 1). Its major mode of action is to reduce hepatic glucose pro-
dose dependent and can usually be avoided by slow titra- duction, which is increased at least twofold in patients with tion and, in some cases, reduction of the dose (9). About type 2 diabetes (32, 36). In a recent study of the mechanism 5% of patients cannot tolerate treatment because of gastro- by which metformin decreases endogenous glucose produc- intestinal side effects (6, 9, 10). The mechanisms of these tion in patients with type 2 diabetes, the increased plasma gastrointestinal side effects remain unclear but probably are glucose level was attributed to a threefold increase in the rate related to accumulation of high amounts of metformin in of gluconeogenesis, as assessed by nuclear magnetic resonance the intestinal tissue (17), with subsequent elevation of local spectroscopy (32). Metformin treatment decreased fasting lactate production. Histologic examination has not re- plasma glucose concentrations by 25% to 30% and reduced vealed changes in the intestinal mucosa in metformin- glucose production (32), findings that are consistent with treated animals (29), indicating a functional rather than a those of other investigators (27, 35). The decrease in glucose structural basis for gastrointestinal symptoms. Ten percent production was attributable to a reduction in the rate of glu- to 30% of patients receiving long-term metformin therapy coneogenesis (32).
develop vitamin B12 malabsorption, as indicated by de- Data from in vivo studies (27, 32, 36) are consistent with creased concentrations of total vitamin B12 and its bioavail- those of in vitro studies demonstrating an inhibitory effect of able form, holotranscobalamin (2, 30). Metformin inter- metformin on gluconeogenesis (37, 38) (Figure 1). For exam-
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Metformin: An Update Update ple, metformin was observed to decrease gluconeogenesis in Figure 1. Mechanisms of metformin action on hepatic glucose
perfused liver, primarily through inhibition of hepatic lactate production and muscle glucose consumption.
uptake (37). Others reported that metformin therapy de-
creased concentrations of adenosine triphosphate in isolated
rat hepatocytes (38). Because adenosine triphosphate is an
allosteric inhibitor of pyruvate kinase, the investigators sug-
gested that the metformin-mediated reduction in hepatic glu-
cose production resulted from increased pyruvate kinase flux.
Metformin also decreases gluconeogenic flux through inhibi-
tion of pyruvate carboxylase–phosphoenolpyruvate carboxyki-
nase activity and possibly through increased conversion of
pyruvate to alanine (34). Metformin also facilitates insulin-
induced suppression of gluconeogenesis from several sub-
stances, including lactate, pyruvate, glycerol, and amino acids
(31), and opposes the gluconeogenic actions of glucagon (39)
(Figure 1).
The exact mechanism through which metformin re- duces hepatic glucose production remains unclear, but itsprimary site of action appears to be hepatocyte mitochon-dria, where it disrupts respiratory chain oxidation of com- Metformin decreases hepatic gluconeogenesis by interfering with respi- plex I substrates (for example, glutamate) (15, 39). Inhibi- ratory oxidation in mitochondria. It suppresses gluconeogenesis fromseveral substrates, including lactate, pyruvate, glycerol, and amino acids.
tion of cellular respiration decreases gluconeogenesis (39) In addition, metformin increases intramitochondrial levels of calcium and may induce expression of glucose transporters and, (Ca⫹⫹), a modulator of mitochondrial respiration. In insulin-sensitive therefore, glucose utilization (40). It is not clear whether tissues (such as skeletal muscle), metformin facilitates glucose transportby increasing tyrosine kinase activity in insulin receptors and enhancing metformin acts on mitochondrial respiration directly by glucose transporter (GLUT) trafficking to the cell membrane. ADP ⫽ slow permeation across the inner mitochondrial membrane 䢇䢇䢇; ATP ⫽ 䢇䢇䢇; Ca⫹⫹ ⫽ intracellular calcium levels; OAA ⫽ (39) or by unidentified cell-signaling pathways (15). It has 䢇䢇䢇; PEP ⫽ phosphoenolpyruvate; Pi ⫽ 䢇䢇䢇; TK ⫽ 䢇䢇䢇.
been suggested that biguanides bind specifically and com-petitively to divalent cation sites on proteins, thus interfer- cogen synthesis (47) (Figure 1). Thus, metformin has met-
ing with intracellular handling of calcium ([Ca2⫹]i) (41, abolic effects on insulin-sensitive tissues that may 42) especially in the mitochondria (41). Davidoff and col- contribute to its glucose-lowering effect.
leagues (41) showed that even small doses of biguanides Metformin has been shown to reduce free fatty acid increase the rates of [Ca2⫹]i uptake in isolated hepatic oxidation by 10% to 30% (25, 31–33). Elevated levels of mitochondria, where [Ca2⫹]i serves as a potent activator of free fatty acid are commonly seen in diabetes and obesity mitochondrial respiration (Figure 1). This effect was
(48), and they contribute to increased hepatic glucose pro- shown at biguanide concentrations as low as 5 to 10 ␮m duction and development of insulin resistance (49, 54) (41), levels that are expected in the liver with antihypergly- (Figure 2). Increased fatty acid oxidation inhibits key en-
cemic doses of the drug and are 20- to 50-fold lower than zymes of the glycolytic pathway by accumulation of acetyl those that inhibit mitochondrial respiration. In several tis- coenzyme A and citrate, by-products of free fatty acid ox- sues, including skeletal muscle and adipocytes, metformin idation (51). Increased glucose 6-phosphate concentra- facilitates trafficking of glucose transporters 4 and 1 to the tions, in turn, inhibit the hexokinase enzyme, resulting in plasma membrane (25, 31, 43). Moreover, metformin may reduced glucose uptake and oxidation (51). In addition, increase the glucose transport capacity of glucose trans- free fatty acid independently inhibits insulin receptor sub- porter 4, and to some extent, glucose transporters 1 (31).
strate-1–associated PI3-kinase activity (52) and subse- The effects of metformin on peripheral insulin-sensi- quently attenuates transmembrane glucose transport (48) tive tissues require the presence of insulin for its full action.
(Figure 2). By decreasing free fatty acid levels, metformin
Metformin enhances most of the biological actions of in- not only improves insulin sensitivity but may also help sulin, including glucose transport and glycogen and lipid correct impaired insulin secretion by ␤-cells (53). Met- synthesis, in persons with preexisting insulin resistance formin has no direct effect on ␤-cell function (9), but it (31). It facilitates glucose transport in cultured skeletal can improve insulin secretion that has been altered by muscle in the absence of insulin (44, 45). Metformin acti- long-term exposure to free fatty acid or hyperglycemia vates insulin and tyrosine kinase activity in insulin-like (glucose toxicity) (53).
growth factor-1 receptor of vascular smooth-muscle cells Metformin may also improve hyperglycemia by attain- independently of insulin action (46). The drug activates ing high concentrations in the small intestine (17, 31) and tyrosine kinase in Xenopus oocytes, with subsequent stim- decreasing intestinal absorption of glucose (29, 54), an ac- ulation of inositol 1,4,5-triphosphate production and gly- tion that may contribute to decreased postprandial blood 2 July 2002 Annals of Internal Medicine Volume 137 • Number 1 E-27
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Update Metformin: An Update Figure 2. Metformin and fatty acids.
Metformin inhibits fatty acid (FA) production and oxidation, thereby reducing fatty acid–induced insulin resistance and hepatic glucose production.
CoA ⫽ coenzyme A; CPT ⫽ 䢇䢇䢇; FFA ⫽ free fatty acid; GLUT ⫽ glucose transporter; IGF-1 ⫽ 䢇䢇䢇; IRS-1 ⫽ 䢇䢇䢇; OAA ⫽ 䢇䢇䢇; PDH ⫽ 䢇䢇䢇; PFK ⫽ 䢇䢇䢇; PI-3 ⫽ 䢇䢇䢇.
glucose levels (55). It has been speculated that increased Clinically, administration of metformin improves hirsutism glucose consumption in the small intestine of metformin- (11), normalizes menstrual cycles (11, 12, 57, 59), and in- treated patients may prevent further glucose transport to duces ovulation (57, 59) in a substantial number of patients the hepatic circulation (29).
with the polycystic ovary syndrome.
In summary, metformin decreases hepatic glucose pro- duction through inhibition of gluconeogenesis and possi- EFFECT OF METFORMIN TREATMENT ON
bly glycogenolysis and improves peripheral insulin sensitiv- CARDIOVASCULAR MORBIDITY AND MORTALITY
ity. In addition, metformin decreases gastrointestinalglucose absorption and indirectly improves pancreatic In the UKPDS 34, metformin therapy was compared ␤-cell response to glucose by reducing glucose toxicity and with conventional treatment or treatment with sulfonyl- free fatty acid levels.
urea or insulin (5). In this trial, which was designed toachieve fasting plasma glucose levels less than 6 mmol/L(⬍108 mg/dL), 342 patients with newly diagnosed type 2 EFFECT OF METFORMIN IN THE POLYCYSTIC OVARY
diabetes were allocated to receive metformin treatment and 951 patients were allocated to receive either chlorpropam- Hyperinsulinemia reflecting insulin resistance is a com- ide, glibenclamide, or insulin. The control group included mon feature in lean and obese patients with the polycystic 411 overweight diabetic patients who were randomly as- ovary syndrome (11, 56, 57). Hyperinsulinemia contributes signed to conventional therapy, primarily with diet alone, directly to excessive testosterone production by the ovaries which resulted in suboptimal glycemic control. During 10 (56) and decreased synthesis of sex hormone– binding globu- years of follow-up, both drug-treated groups achieved lin in the liver (11, 58), thereby increasing levels of total and equal degrees of glycemic control (median hemoglobin A1c free testosterone. Metformin therapy increases insulin sensitiv- value of 0.074 [7.4%]), whereas the conventionally treated ity and decreases insulin levels in patients with the polycystic group had a median hemoglobin A1c value of 0.08 (8.0%) ovary syndrome (56, 57, 59). Improvement of hyperinsulin- (5). Compared with the conventionally treated group, emia is associated with decreased levels of total and free tes- metformin-treated patients had a risk reduction of 32% tosterone (11, 12, 57, 59) and increased estradiol (12) levels.
any diabetes-related end point, 39% for myocardial infarc- E-28 2 July 2002 Annals of Internal Medicine Volume 137 • Number 1
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Metformin: An Update Update tion, 42% for diabetes-related death, and 36% for all-cause poorly controlled diabetes (48) contribute not only to de- mortality (5). These differences may be partially explained velopment of insulin insensitivity but also to increased syn- by differences in the degree of glycemic control between thesis and secretion of very low-density lipoprotein (69).
the metformin and diet groups. In the UKPDS 35 (60), Elevated triglyceride levels inhibit degradation of apopro- the risk for cardiovascular events, stroke, and all-cause tein B in the liver and lead to increased assembly of very death was closely related to the degree of glycemia in dia- low-density lipoprotein and smaller, denser LDL particles betic patients. In that study, each 1% reduction in the (69). Excessive generation of reactive oxygen species and hemoglobin A1c value during treatment of type 2 diabetes free radicals (such as peroxynitrates) by cardiovascular tis- was associated with a reduction of 21% in diabetes-related sue, in combination with increased nonenzymatic glycation deaths, 14% in the incidence of myocardial infarction, of lipoproteins (glycooxidation), leads to formation of 12% in fatal and nonfatal strokes, and 16% in heart failure atypical glycooxidized LDL particles. These particles bind (60). Nevertheless, metformin was more effective than sul- poorly to classic LDL receptors but have high affinity for fonylureas or insulin in reducing rates of any diabetes- "scavenger" receptors, which are located predominantly on related end point, all-cause mortality, and stroke, even macrophages (63). Accumulation of glycooxidized small, though both agents decreased hemoglobin A1c values dense LDL particles converts macrophages into foam cells, equally (5). These observations suggest that metformin which are essential participants in the early steps of athero- might have additional cardiovascular protective actions be- sclerotic plaque formation (63). Compared with the gen- yond its antihyperglycemic properties. However, data indi- eral population, diabetic persons have a twofold to fourfold cate that metformin in combination with sulfonylurea increased risk for cardiovascular disease at any cholesterol might increase cardiovascular mortality in patients with level (70), which indicates a more aggressive type of dys- type 2 diabetes (5, 61). In those studies, metformin was lipidemia. Furthermore, decreasing cholesterol and triglyc- not used as an initial therapy but rather was added to eride levels has been shown to be particularly beneficial in treatment when sulfonylurea therapy failed. Patients taking patients with diabetes (70, 71). In addition, hypertriglyc- combination therapy with metformin and sulfonylurea eridemia may be an independent risk factor for cardiovas- tended to have long-standing poorly controlled diabetes cular disease in patients with type 2 diabetes (72). Met- before addition of the biguanide (62). Moreover, they had formin has major effects on lipid metabolism in patients greater obesity (61), which could independently increase with insulin resistance. It decreases plasma levels of free mortality. Therefore, the reported increase in risk for car- fatty acid (20, 73) and oxidation of these acids by tissue diovascular disease in patients treated with combination (25, 28, 32); it decreases levels of triglycerides (2, 10, 20, therapy might reflect selection bias attributable to the natural 55, 74) and, therefore, very low-density lipoprotein (20).
history of long-standing diabetes rather than to adverse effects Metformin therapy decreases levels of total cholesterol (2, of this combination.
68, 74) and LDL cholesterol (2, 68, 74) while maintaining(68, 74) or increasing (2, 20, 55, 57, 67) levels of high-density lipoprotein cholesterol. Metformin decreases oxida- MECHANISM OF THE CARDIOPROTECTIVE ACTION OF
tive stress and reduces lipid oxidation (75) by lowering plasma glucose levels (2). Taken together, these observa- Insulin resistance, a cornerstone of type 2 diabetes and tions suggest that the beneficial effects of metformin on the metabolic cardiovascular syndrome, is commonly asso- lipoprotein metabolism may contribute to its protective ciated with hypertension, abdominal obesity, atherogenic effects against cardiovascular disease.
dyslipidemia, and vascular dysfunction, all of which con- Metformin has also been shown to lessen hypercoagula- tribute greatly to the development of accelerated athero- tion and increase fibrinolysis in insulin-resistant states by de- sclerosis (63). Hyperinsulinemia reflects insulin resistance creasing levels of plasminogen activator inhibitor-1 (76, 77) and may be an independent risk factor for coronary artery and increasing tissue plasminogen activator activity (74).
disease (64 – 66). Metformin, an insulin-sensitizing agent, Therapy with metformin also reduces thrombogenic propen- decreases insulin resistance in patients with (20, 31, 55) sity by decreasing levels of tissue plasminogen activator anti- and without (11, 12, 57, 67) diabetes, thus effectively re- gen (78) and von Willebrand factor (78). In the Biguanides ducing baseline and glucose-stimulated insulin levels (12, and the Prevention of the Risk of Obesity study, 457 nondi- 20, 55, 57, 67).
abetic patients with visceral obesity (body mass index of 32.5 Several studies have shown that metformin improves kg/m2) were randomly assigned to treatment with diet or met- lipoprotein profiles in diabetic patients (2, 10, 20, 55, 68).
formin (850 mg twice daily) (78). Weight loss was associated Dyslipidemia in diabetes is characterized by hypertriglycer- with a 30% to 40% decrease in plasminogen activator inhib- idemia (increased levels of very low-density lipoprotein itor-1 activity, regardless of the method used, whereas met- cholesterol); decreased levels of high-density lipoprotein formin produced significantly larger decreases in von Wille- cholesterol; and elevated levels of small, dense atherogenic brand factor levels than did diet therapy (78). Furthermore, low-density lipoprotein cholesterol (LDL) particles. The metformin therapy decreased platelet aggregation in diabetic increased levels of free fatty acid that occur in obesity and patients treated with 1700 mg/d (79). Thus, metformin ther- 2 July 2002 Annals of Internal Medicine Volume 137 • Number 1 E-29
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Update Metformin: An Update Table. Direct and Indirect Cardiovascular Protective Effects of
over, insulin is responsible for the normal handling of di- valent cations in vascular smooth muscle (92). Those pro-cesses are altered in insulin resistance. Impaired vascular Decreases hyperglycemia insulin action may result in impaired nitric oxide– Improves diastolic functionDecreases total cholesterol levels dependent vascular relaxation, decreased sodium pump ac- Decreases very low-density lipoprotein cholesterol levels tivity, and increased levels of [Ca2⫹]i in vascular smooth Decreases low-density lipoprotein cholesterol levels muscle in patients with type 2 diabetes (14, 63, 92). These Increases high-density lipoprotein cholesterol levelsDecreases oxidative stress abnormalities in divalent cation and nitric oxide metabo- Improves vascular relaxation lism appear to play a role in the increased vascular resis- Decreases plasminogen activator inhibitor-1 levels tance and impaired vasorelaxation that characterize hyper- Increases tissue plasminogen activator activityDecreases von Willebrand factor levels tension, which frequently occurs in diabetic patients (92).
Decreases platelet aggregation and adhesion Several reports indicate an antihypertensive effect of metformin in animals (88, 93–95) and humans (74, 96).
In contrast, no effect of metformin on blood pressure was apy appears to lessen the hypercoagulability and exaggerated reported in other human studies (1, 2, 23). Careful 24- platelet aggregation and adhesion in diabetic patients (Table).
hour ambulatory studies may better characterize the effectsof metformin on blood pressure in diabetic patients (89).
Potential mechanisms of antihypertensive action of met- ETFORMIN AND DIABETIC CARDIOMYOPATHY
formin are complex and include both insulin-dependent Persons with diabetes have a high prevalence of con- and insulin-independent vasodilatory actions (Figure 3).
gestive heart failure (80) secondary to diabetic, hyperten- Acute administration of metformin to rat tail arteries in- sive, and ischemic changes in the myocardium. Diabetic creases repolarization and causes subsequent artery relax- cardiomyopathy, a unique clinical entity, is characterized ation (97) through reduction in agonist-induced increase by structural changes in the myocardium (fibrosis) and in intracellular levels of [Ca2⫹]i vascular smooth muscle functional alterations in diastolic relaxation and ventricular (46, 94). This attenuation of [Ca2⫹]i responses may be compliance (81– 84) (Figure 3). Delayed diastolic relax-
secondary to increased nitric oxide production by vascular ation in diabetic cardiomyopathy is related to diminished smooth muscle during exposure to metformin (94). In- removal of [Ca2⫹]i from cardiomyocytes after systolic con- deed, nitric oxide has been shown to decrease vascular traction (82, 83). Hyperglycemia has been shown to con- smooth muscle [Ca2⫹]i responses to vasoconstrictor ago- tribute to these functional changes (82– 84), and insulin nists through activation of the cyclic guanosine monophos- resistance also directly contributes to these abnormalities phate pathway (98). Metformin may also reduce [Ca2⫹]i (85). Metformin treatment of streptozotocin diabetic ratscorrects these functional cardiac abnormalities (84, 86),perhaps through tyrosine kinase– dependent increases in Figure 3. Proposed cellular mechanisms of metformin action in
intracellular [Ca2⫹]i removal after systole (84). This car- the vascular smooth-muscle cells and cardiomyocytes.
dioprotective action of metformin was shown to be insulinindependent (84). Moreover, treatment of spontaneouslyhypertensive rats with metformin has been reported to de-crease heart rate (a sympathoinhibitory effect) more thanplacebo (87, 88). Although these findings are of interest,no clinical trials to date have investigated the effect of met-formin on the development and course of congestive heartfailure in diabetic patients.
METFORMIN AND VASCULAR REACTIVITY
Hypertension is often associated with insulin resis- tance (89). Diabetic patients have a higher incidence ofhypertension compared with the general population, andhypertensive persons are more prone to develop diabetes(90, 91). Recently, investigators demonstrated that defec-tive insulin signaling may contribute to increased vascularresistance (92), which is the hallmark of hypertension in In vascular smooth-muscle cells, metformin decreases vasoconstriction by type 2 diabetes (89). Insulin normally acts through the enhancing sodium pump activity and nitric oxide (NO) production, PI3-kinase pathway to activate nitric oxide synthase, en- causing a decrease in intracellular calcium levels (Ca⫹⫹). Metforminimproves diastolic relaxation by enhancing calcium removal from cardio- hance sodium pump activity in vascular smooth muscle, myocytes after systole. ATP ⫽ 䢇䢇䢇; CGMP ⫽ 䢇䢇䢇; GTP ⫽ and increase glucose transmembrane transport (63). More- 䢇䢇䢇; K-ATP ⫽ 䢇䢇䢇.
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Metformin: An Update Update by increasing the activity of the sodium–adenosine triphos- Grant Support: By the National Institutes of Health (RO1-HL-63904-
phatase pump (99) and enhancing adenosine triphosphate– 01), the Veterans Affairs Merit Review, and the American Diabetic As- sensitive K⫹channels (100) (Figure 3). The ability of met-
formin to stimulate sodium pump activity is probably Requests for Single Reprints: James R. Sowers, MD, State University
linked to increased lactate production in vascular smooth of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, muscle (99, 101). Metformin may have central antihyper- Box 1205, Brooklyn, NY 11203; e-mail, [email protected]
tensive actions, because infusion of this drug into lateralcerebral ventricles of spontaneous hypertensive rats pro- Current Author Addresses: Drs. Kirpichnikov, McFarlane, and Sowers:
duced dose-dependent decreases in mean arterial pressure, State University of New York Health Science Center at Brooklyn, 450 heart rate, and renal sympathetic nerve activity (88).
Clarkson Avenue, Box 1205, Brooklyn, New York 11203.
Even a small elevation in blood pressure significantly Current author addresses are available at www.annals.org.
increases death from cardiovascular disease and risk formyocardial infarction, stroke, and congestive heart failurein diabetic persons (102). Each 10 –mm Hg increase in systolic blood pressure produces a 15% increase in the rate 1. Hermann LS, Scherste´n B, Bitze´n PO, Kjellstro¨m T, Lindga¨rde F, Melander
of death related to diabetes and an 11% increase in inci- A. Therapeutic comparison of metformin and sulfonylurea, alone and in various
combinations. A double-blind controlled study. Diabetes Care. 1994;17:1100-9.
dence of myocardial infarction, 19% in stroke, and 12% in congestive heart failure (101). Therefore, even a minimal 2. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-
reduction in blood pressure during treatment with met- insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group.
formin may contribute to a significant decrease in diabetes- N Engl J Med. 1995;333:541-9. [PMID: 7623902] related morbidity and mortality.
3. United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacyof randomly allocated diet, sulphonylurea, insulin, or metformin in patients withnewly diagnosed non-insulin dependent diabetes followed for three years. BMJ.
1995;310:83-8. [PMID: 7833731] 4. Johansen K. Efficacy of metformin in the treatment of NIDDM. Meta-anal-
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Doi:10.1016/j.cell.2007.11.047

NFATc1 Balances Quiescence andProliferation of Skin Stem CellsValerie Horsley,Antonios O. Aliprantis,Lisa Polak,Laurie H. Glimcher,and Elaine Fuchs,1Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University,New York, NY 10065, USA2Department of Infectious Diseases and Immunology, Harvard School of Public Health, Boston, MA 02115, USA3Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA*Correspondence: DOI 10.1016/j.cell.2007.11.047