The glucose-lowering effect of metformin, monotherapy or in combination, has been extensively reviewed (70-72). In a meta-analysis (73) all randomized, controlled clinical trials comparing metformin with placebo (29,62,74-80) and sulfonylurea (62,74,81-87) were evaluated. The weighted mean difference between metformin and placebo after treatment (median treatment duration 4.5 months) for fasting blood glucose was -2.0 mM and for HbA1c -0.9%. Body weight was not significantly changed after treatment. Sulfonylureas and metformin lowered blood glucose (-2.0 and -1.8 mM, respectively) and HbA1c (-1.1% and -1.3%, respectively) equally (median treatment duration 6 months). However, while after sulfonylurea treatment body weight increased by 2.9 kg there was a decrease of 1.2 kg after metformin. In a retrospective study of 9875 patients with type 2 diabetes mellitus who attended a large health maintenance organization metformin treatment improved the mean HbA1c by 1.41% over a 20 months period (88).
Among obese patients allocated intensive blood glucose control within in the UKPDS, metformin showed a significantly greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint, all-cause mortality, and stroke (74). In summary, metformin is as effective as sulfonylureas in improving glycemic control but, especially in overweight/obese patients, advantageous with respect to body weight, diabetes-related endpoints, and frequency of hypoglycemia.
In addition to improving glycemic control metformin has been shown to reduce serum lipid levels. Metformin treatment results in a moderate (10-20%) reduction in circulating triglyceride levels, particularly in patients with marked hypertriglyceridemia and hypergly-cemia (24,36,89), and also in nondiabetic subjects (90,91). This has been attributed to a reduction in hepatic very low-density lipoprotein (VLDL)-synthesis (36,78,92). Small (5-10%)
decreases in total circulating cholesterol have also been reported (67,75-77), which were essentially attributed to reductions in LDL levels (93-95) since high-density lipoprotein (HDL)-cholesterol were either increased (90) or unchanged (95).
In addition to the improvement of the lipid profile, metformin appears to have potentially beneficial hemostaseological effects. Fibrinolysis is increased (91,93,94) and the fibrinolysis inhibitor plasminogen-activator inhibitor 1 (PAI-1) is decreased (78,91,96).
Moreover, a decrease in platelet aggregability and density has been demonstrated (82,97). These additional effects of metformin that have been extensively reviewed elsewhere (70,71) may explain the advantage of metformin over sulfonylurea or insulin treatment with respect to macrovascular endpoints shown in the UKPDS (74), and in other randomized clinical trials that have been recently reviewed in a Cochrane meta-analysis (98).
Combination Therapies: Metformin Plus Sulfonylureas, Metformin Plus Glitazones, and Metformin Plus Insulin
Metformin is also used in combination with other antihyperglycemic agents. Because of its unique mechanisms of action a synergistic effect on glycemic control has been observed in combination with sulfonylureas (62,99,100), glitazones (101,102), and insulin where a dosesparing effect was consistently demonstrated (48-50,103-105). Interestingly, in patients in whom sulfonylurea therapy has failed to satisfactory control glycemic, the combination of bedtime NPH-insulin. with metformin was advantageous compared to other combinations (105). In contrast to insulin alone, insulin plus sulfonylurea, and sulfonylurea alone, combining bedtime NPH-insulin with metformin achieved a decrease in HbA1c without significant weight gain (104,105).
While mild gastrointestinal disturbances are the most common side effects, lactic acidosis, though rare, is the most serious side effect of metformin treatment (106). In 9875 patients one case of probable lactic acidosis was observed in 20 treatment months (88). The incidence of lactic acidosis is 10 to 20 times lower than with phenformin. This is explained by the necessity to hydroxylate phenformin prior to renal excretion, a step which is genetically defective in 10% of whites (107,108). Metformin, in contrast, is excreted unmetabolized. In addition, in contrast to phenformin (109), metformin does neither increase peripheral lactate production nor decrease lactate oxidation (24,25) making lactate accumulation unlikely.
One study investigating individual cases of metformin-associated lactic acidosis showed that in these patients metformin should either have never been started or discontinued with the onset of acute illness (110). Thus, strict adherence to the exclusion criteria of metformin treatment [renal (creatinine clearance < 60 mL/min) and hepatic disease, cardiac (NYHA III-IV) or respiratory insufficiency, severe infection, alcohol abuse, history of lactic acidosis, pregnancy, use of intravenous radiographic contrast) should minimize the risk of metformin-induced lactic acidosis.
As recently recommended in a consensus statement of the American Dental Association (ADA) and the European Association for the Study of Diabetes (EASD) metformin should be initiated together with diet and exercise when patients have been diagnosed with type 2 diabetes (111). Metformin appears to be the drug of choice to start pharmacological treatment in insulin resistant and overweight/obese diabetic subjects (70,74,112). However, since the antihyperglycemic effects of metformin are similar in lean and obese subjects it can also be recommended as first-line treatment in the absence of obesity. It has been shown that the maximal antihyperglycemic effect of metformin is obtained using 2g/day (Fig. 6) (113). Addition of metformin to sulfonylureas in patients with secondary sulfonylurea failure appears reasonable in view of their synergistic mechanisms of action and has been shown to improve glycemic control. Furthermore, especially in overweight/obese patients the addition
FIGURE 6 Effect of increasing metformin dose per day on fasting plasma glucose and HbA1c in type 2 diabetic patients. Source: From Ref. 113.
of metformin to insulin is advantageous compared to insulin alone (114). Moreover, in the Diabetes Prevention Program metformin has been shown to reduce the risk to develop type 2 diabetes in subjects with IGT by 31% (112), but it is not yet approved for use in subjects with IGT.
The above-described favorable effects of metformin in patients with type 2 diabetes have lead to the widespread recommendation in evidence-based guidelines in many countries to use metformin as first-line drug.
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