Metformin: An Update

By Dmitri Kirpichnikov, Samy I McFarlane, J. Sowers. Annals of Internal Medicine, 2002

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Insulin resistance contributes greatly to development of cardiovascular disease in patients with the metabolic syndrome and its extreme presentation, type 2 diabetes mellitus. Therefore, treatment with an insulin-sensitizing agent, such as metformin, in patients with type 2 diabetes mellitus may correct several of the primary pathophysiologic abnormalities of the metabolic syndrome. In diabetic patients, metformin appears to provide cardiovascular protection that cannot be attributed only to its antihyperglycemic effects. These additional cardioprotective effects in these patients may be related to the favorable actions of metformin on lipid metabolism, vascular smooth-muscle and cardiomyocyte intracellular calcium handling, endothelial function, hypercoagulation, and platelet hyperactivity. We discuss known mechanisms by which metformin exerts its beneficial glycemic and cardiovascular actions. Clinical Role of Metformin Metformin, an insulin-sensitizing biguanide used to treat type 2 diabetes, has been shown to be as effective as insulin or sulfonylureas when used as monotherapy (1-5). In conjunction with diet, metformin reduces fasting glucose concentration by 2.78 to 3.90 mmol/L (50 to 70 mg/dL), which corresponds to a 1.3% to 2.0% reduction in hemoglobin A1c values (1, 2, 4, 6-8). The magnitude of plasma glucose reduction is related to pretreatment glucose levels (7, 9). The efficacy of metformin monotherapy has been shown to be independent of age, body weight, ethnicity, duration of diabetes, and insulin and C-peptide levels (1, 2). Metformin may have special benefits in overweight patients with type 2 diabetes. Unlike sulfonylureas, insulin, and thiazolidinediones, metformin does not affect body mass index (1) or decreases body weight in obese patients with (4, 10) and without (11, 12) diabetes. Significant reductions in total body fat and visceral fat have been observed in women with preexistent abdominal or visceral obesity who are treated with metformin (11). Excessive fat localized to the paraintestinal region is a major contributor to the pathogenesis of the cardiovascular metabolic syndrome (13, 14), and the reduction in visceral fat (secondary to weight loss or fat redistribution) may have additional cardiovascular benefits in insulin-resistant persons treated with metformin (13, 14). Weight loss during metformin treatment has been attributed to decreased net caloric intake (15), probably through appetite suppression, an effect that is largely independent of gastrointestinal side effects of metformin (such as nausea and diarrhea) (10). Reduction in hyperinsulinemia related to reduced insulin resistance may have an additive effect on weight reduction in obese insulin-resistant persons (13, 14). At doses of 500 to 1500 mg, metformin has an absolute oral bioavailability of 50% to 60% (16). The drug is not protein bound and therefore has a wide volume of distribution (8), with maximal accumulation in the small-intestine wall (17). Metformin undergoes no modifications in the body and is secreted unchanged by rapid kidney excretion (through glomerular filtration and, possibly, tubular secretion) (8). Impaired kidney function slows elimination and may cause metformin accumulation (18). The H2-blocker cimetidine competitively inhibits renal tubular secretion of metformin, significantly decreasing its clearance and increasing its bioavailability (16, 19). Metformin as a Part of Combination Therapy Metformin has been shown to be effective in combination with insulin, sulfonylureas (2, 10, 20, 21), and thiazolidinediones (22). This finding is important because single-drug therapy often fails to maintain normoglycemia, particularly as diabetes progresses (23, 24). As seen in the United Kingdom Prospective Diabetes Study (UKPDS), 50% of patients treated with diet or a single antidiabetic drug achieved the target hemoglobin A1c value of less than 7% after 3 years of follow-up; after 9 years, only 25% maintained this goal (24). As diabetes progresses and treatment with maximal doses of sulfonylurea fails, addition of metformin significantly improves glycemic control (2). In the UKPDS trial, combination therapy tended to control glycemia more effectively than monotherapy (hemoglobin A1c value, 0.075 [7.5%] versus 0.081 [8.1%]) (23). Practical Considerations in Metformin Therapy The ideal patient for initiation of metformin treatment would be an obese person with type 2 diabetes mellitus who has normal kidney function (creatinine concentration <133 m d/L [<1.5 mg/dL] in men and <124 m d/L in women, or creatinine clearance >1.17 mL/s without coexistent symptomatic congestive heart failure or a hypoxic respiratory condition) (9, 16, 25). Contraindications to metformin therapy are liver failure, alcoholism, and active moderate to severe infection (9, 25); these conditions predispose to development of lactic acidosis, either by increased production or decreased metabolism of lactic acid (9, 16-18, 25). Administration of radiocontrast material to a patient with diabetes may worsen already-compromised kidney function and cause accumulation of metformin, leading to toxic levels of drug. Furthermore, administration of general anesthesia may cause hypotension, which leads to renal hypoperfusion and peripheral tissue hypoxia with subsequent lactate accumulation (25-28). Therefore, if administration of radiocontrast material is required or urgent surgery is needed, metformin should be withheld and hydration maintained until preserved kidney function is documented at 24 and 48 hours after the intervention (9, 26-28). Metformin should be used with caution in elderly patients, whose reduced lean body mass may lead to misleading low creatinine concentrations that fail to reflect decreased glomerular filtration rates (9, 25-28). Metformin therapy should be initiated with a single dose of medication (usually 500 mg) taken with the patient's largest meal to prevent gastrointestinal symptoms. Gastrointestinal symptoms generally disappear within 2 weeks of treatment (10, 11). Medication doses may be increased by 500-mg increments every 1 to 2 weeks, as indicated by glycemic control, until a desirable blood glucose level or the maximal recommended daily metformin dose of 2550 mg is reached (2, 25). The hypoglycemic effect of metformin is dose related, and a plateau of hypoglycemic action is achieved at a daily dose of 2000 mg (6). Side effects of metformin are mostly limited to digestive tract symptoms, such as diarrhea, flatulence, and abdominal discomfort (1, 6, 8-10). These symptoms are dose dependent and can usually be avoided by slow titration and, in some cases, reduction of the dose (9). About 5% of patients cannot tolerate treatment because of gastrointestinal side effects (6, 9, 10). The mechanisms of these gastrointestinal side effects remain unclear but probably are related to accumulation of high amounts of metformin in the intestinal tissue (17), with subsequent elevation of local lactate production. Histologic examination has not revealed changes in the intestinal mucosa in metformin-treated animals (29), indicating a functional rather than a structural basis for gastrointestinal symptoms. Ten percent to 30% of patients receiving long-term metformin therapy develop vitamin B12 malabsorption, as indicated by decreased concentrations of total vitamin B12 and its bioavailable form, holotranscobalamin (2, 30). Metformin interferes with mucosal-cell intracellular calcium handling, thus disrupting calcium-dependent absorption of vitamin B12 in the ileum (30). Such decreases in vitamin B12 levels rarely have clinical significance (2, 9). Development of hypoglycemia during metformin monotherapy is rare because metformin only partially suppresses gluconeogenesis in the liver and does not stimulate insulin production (9, 31). Lactic acidosis is a life-threatening complication of biguanide therapy that carries a mortality rate of 30% to 50% (28). Metformin therapy may increase blood lactate levels (1) and is occasionally associated with development of lactic acidosis (2, 28). The estimated incidence of metformin-associated lactic acidosis is 0.03 cases per 1000 patient-years (25), which is 10 to 20 times lower than that seen with phenformin therapy (28). Development of lactic acidosis appears to be unrelated to plasma metformin concentrations (28), and even in persons with chronic renal insufficiency, metformin accumulation does not necessarily lead to lactic acidosis (18). Development of lactic acidosis is almost always related to coexistent hypoxic conditions that are probably responsible for the associated high mortality rate. In one report, 91% of patients who developed lactic acidosis while being treated with metformin had a predisposing condition, such as congestive heart failure, renal insufficiency, chronic lung disease with hypoxia, or age older than 80 years (26). Thus, patients with compromised renal function or coexistent hypoxic conditions should not be given metformin. Chronic or acute intake of large amounts of alcohol may potentiate the effect of metformin on lactate metabolism. A careful history of alcohol use is therefore important before starting metformin therapy (26, 27). Mechanisms of Antihyperglycemic Action of Metformin The glucose-lowering effects of metformin are mainly a consequence of reduced hepatic glucose output (primarily through inhibition of gluconeogenesis and, to a lesser extent, glycogenolysis) and increased insulin-stimulated glucose uptake in skeletal muscle and adipocytes (25, 27, 31-35) (Figure 1). Its major mode of action is to reduce hepatic glucose production, which is increased at least twofold in patients with type 2 diabetes (32, 36). In a recent study of the mechanism by which metformin decreases endogenous glucose production in patients with type 2 diabetes, the increased plasma glucose level was attributed to a threefold increase in the rate of gluconeogenesis, as assessed by nucl

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Physiology

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