Table 2. Pharmacological Differences Among Metformin, Sulfonylureas, Acarbose, Troglitazone, and Repaglinide18-23

Characteristic       Metformin Sulfonylureas   Acarbose Troglitazone Repaglinide Mechanism of action  hepatic glucose production and gluconeogenesis peripheral glucose utilization intestinal glucose absorption   pancreatic insulin secretion digestion of complex carbohydrates and disaccharides to absorbable monosaccharides hepatic glucose production and gluconeogenesis peripheral glucose utilization pancreatic insulin secretion Blood glucose levels in hyperglycemic state only in hyperclycemic and normoglycemic states   in hyperclycemic state only in hyperclycemic state only in hyperclycemic and normoglycemic states Plasma insulin levels   or unchanged Unchanged Body weight or unchanged   or unchanged Unchanged Not known Plasma lipids in type 2 diabetes patients LDL cholesterol, total cholesterol, triglycerides or no effects on HDL cholesterol No significant effects No consistent effects LDL cholesterol, total cholesterol, triglycerides or no effects on HDL cholesterol   No significant effects  = Increased/enhanced; = Decreased/suppressed

PHARMACOLOGY OF
ANTIDIABETIC AGENTS
Antidiabetic agents available for the treatment of type 2 diabetes include the sulfonylureas, the biguanide metformin, the -glucosidase inhibitor acarbose, the thiazolidinedione troglitazone, and the meglitinide repaglinide. Although these therapies are effective antidiabetic agents, their mechanisms of action differ (Table 2).^18-23

Sulfonylureas
Sulfonylureas work predominantly through pancreatic mechanisms, although extrapancreatic mechanisms may also contribute to their antihyperglycemic effects.^14,24

Pancreatic Effects
Sulfonylureas stimulate the release of insulin from pancreatic -cells. Studies in which sulfonylureas have been administered to pancreatectomized animals and to patients with type 1 (insulin-dependent) diabetes mellitus and pancreatic diabetes have demonstrated that these agents exhibit a hypoglycemic effect only if a functional pancreas is present.¹⁹

The mechanism by which sulfonylureas stimulate insulin secretion appears to be receptor-mediated. Insulin secretion is initiated when the drug binds to a cell surface receptor on the pancreatic -cell.^14,19 This interaction inhibits the efflux of potassium ions and causes depolarization. This depolarization then causes a calcium channel to open, which in turn causes an influx of calcium, leading to the release of insulin.

Extrapancreatic Effects
Although it has been proposed that numerous extrapancreatic effects may contribute to the hypoglycemic effect of sulfonylureas, it is unlikely that these effects are clinically relevant. Two mechanisms in particular have been reported^19,25 involving the potentiation of insulin action—on the liver to decrease hepatic glucose production and on skeletal muscle and adipose tissue to improve carbohydrate transport. However, the relevance of these actions to the overall efficacy of the sulfonylureas is modest.

Metformin
Unlike the sulfonylureas, which are classified as hypoglycemic agents, metformin is more accurately described as an antihyperglycemic agent because it does not cause hypoglycemia when used alone in type 2 diabetic patients. Metformin lowers plasma glucose levels in type 2 diabetes by reducing insulin resistance. This pharmacodynamic action partially reverses the underlying pathophysiology of Syndrome X. Metformin monotherapy-induced reduction of hyperglycemia is similar to that achieved with sulfonylureas in obese and nonobese patients.^22,26-29

Hepatic Glucose Production (HGP)
As a result of insulin resistance, excessive HGP is a major feature of type 2 diabetes and a major contributor to the hyperglycemic condition.^3,30 Metformin reduces HGP by 9–30% in patients receiving metformin, relative to baseline or placebo, usually after administration of metformin dosages ranging from 1,000 to 2,550 mg/day for up to 3 months.^31-36 This decrease in HGP is attributed to an inhibition of gluconeogenesis.^14,18,36

Peripheral Glucose Utilization
Peripheral insulin-mediated glucose utilization is 20–40% lower in diabetic individuals compared with nondiabetic controls.^29,30 The administration of metformin 0.5–3 g/day for up to 3 months increased peripheral glucose utilization by 18–29% relative to baseline or placebo.^33,37-41 This improvement in glucose utilization occurs in skeletal muscle, in fat and intestinal tissue, and possibly in erythrocytes.^18,30

Other Antihyperglycemic Effects
Although metformin has been shown to decrease intestinal glucose absorption, this does not sufficiently account for the significant antihyperglycemic effect of metformin.⁴²

Evidence from studies conducted in animals and cultures of skeletal muscle taken from insulin-resistant patients indicates that metformin acts at the cellular level to enhance glucose transport by stimulating glucose transporter activity.^38,43,44 Again, the clinical significance of this observation is unknown.

Acarbose
Acarbose is the first drug in a new class of antidiabetic agents, the -glucosidase inhibitors, that has recently become available in the United States for the treatment of type 2 diabetes. It exerts its antidiabetic effect by delaying the digestion of complex carbohydrates and disaccharides (e.g., starch) to absorbable monosaccharides (e.g., glucose). This is accomplished by reversible inhibition of the -glucosidase enzymes (e.g., sucrase and maltase) that are located in the duodenum.^16,20 In type 2 diabetic patients, this enzyme inhibition delays glucose absorption following ingestion of complex carbohydrates.

Acarbose does not appear to have a direct effect on insulin resistance or on insulin-stimulated glucose uptake in humans.²⁰

Troglitazone
Troglitazone is the first drug in another new class of oral antidiabetic agents, the thiazolidinediones. Thiazolidinediones are thought to produce their antidiabetic effect by activating the peroxisome proliferator-activated receptor (PPAR)g, a nuclear receptor that regulates the transcription of several key insulin-sensitive genes involved in controlling glucose and lipid metabolism.²¹ Like metformin, troglitazone alleviates hyperglycemia in type 2 diabetic patients by reducing insulin resistance in peripheral tissues.

Troglitazone monotherapy at dosages of 400 and 600 mg/day increases insulin-mediated glucose disposal (by ~45%) after 6 months of treatment.⁴⁵ A reduction in HGP in type 2 diabetic patients occurred only after administration of the maximum recommended dose of troglitazone (600 mg/day) for 6 months in one study (n = 93)⁴⁵ and after administration of troglitazone (200 mg twice daily) for 6–12 weeks in a much smaller study (n = 11).⁴⁶ The reduction in HGP appears to be secondary to suppression of gluconeogenesis.²¹

The antihyperglycemic effect of troglitazone appears to be intermediate between that of acarbose and that of metformin and the sulfonylureas. Troglitazone monotherapy at doses of 200, 400, and 600 mg/day for 3 months reduced fasting serum glucose by 11, 14, and 15%, respectively, in a dose-response study.⁴⁷ Little additional benefit was gained by increasing the dose to 800 mg/day, at which a 19% reduction in fasting serum glucose was observed. Results of two separate studies in type 2 diabetic patients suggest that troglitazone 400 mg/day achieves equivalent reductions in hyperglycemia as glyburide 12 mg/day after 1 year of treatment⁴⁸ and as metformin 2,000 mg/day after 3 months of treatment.⁴⁹ However, these data need to be confirmed in other trials, particularly the data relating to metformin, as the latter study involved only 28 patients.

Repaglinide
Repaglinide is another first drug of its class, the meglitinides, which are benzoic acid derivatives. The Food and Drug Administration approved it in April 1998 for use alone and in combination with metformin. Repaglinide is an insulin secretagogue with a rapid onset of action and a short half-life.

The few clinical trials have been summarized in The Medical Letter.^23,50 When compared to the sulfonylurea glyburide, repaglinide was less effective in lowering fasting plasma glucose but more effective in lowering postprandial glucose. Similar effects on hemoglobin A_1c were seen. A lowering of HbA_1c of between 1.3 and 1.9% can be expected, similar to the sulfonylureas.

Repaglinide works directly on the pancreatic -cell and thus is ineffective in type 1 diabetes. When used in combination with metformin, repaglinide is synergistic, as would be expected given the two drugs’ different mechanisms of action.⁵¹

Side effects in the clinical trials were not significantly different between the drug and placebo, with the exception of hypoglycemia, which in our limited experience appears to occur less frequently than with the sulfonylureas. Repaglinide needs to be taken with meals, with dosing dependent on initial HbA_1c and clinical response. Initial doses range between 0.5 and 2 mg, with total daily dose not to exceed 16 mg.

Secondary Pharmacological Effects Effect on Insulin Levels
In contrast to sulfonylureas, neither metformin nor troglitazone causes hyperinsulinemia.^18,21,29,52 A reduction in insulin levels has been observed when metformin was administered alone or in combination with a sulfonylurea.^27,53 In a 3-year study comparing diet, insulin, metformin, and sulfonylureas, mean fasting plasma insulin levels significantly increased (P<0.001) in all but the metformin treatment group.²⁹ In the same trial, significant reductions (-1.6 µU/L; P<0.001) in fasting plasma insulin levels were found in overweight patients receiving metformin, compared with overweight patients utilizing a change in diet alone.

Troglitazone generally reduces fasting ^45,47,54,55 and postprandial⁴⁶plasma insulin levels. Reductions from baseline in plasma insulin levels of 5–31% were reported after 3 months of treatment with troglitazone dosages ranging from 200 to 800 mg/day.^47,54 However, in one placebo-controlled 6-month monotherapy study, only the 600 mg/day dose (the maximum recommended in the United States) produced significant reductions (P < 0.01) in plasma insulin compared with placebo.⁵⁵ In combination with a sulfonylurea (glyburide), troglitazone 600 mg/day produced significant reductions in insulin levels compared with placebo after 6 weeks’ treatment.⁵⁶

Clinical trials are not entirely consistent with regard to the effect of acarbose on plasma insulin. Placebo-controlled and noncomparative investigations have reported changes in fasting or postprandial insulin levels, but these changes were not statistically significant.^20,57 Of three randomized double-blind studies, two reported substantial decreases in postprandial insulin levels compared with placebo.^58-60

Effect on Lipids
Dyslipidemia, including decreased plasma HDL cholesterol levels, is usually present in those with poorly controlled type 2 diabetes. As these abnormalities are now recognized to be major contributors to the development of arterial vascular disease, there is significant interest in the beneficial effects of antidiabetic agents, particularly those that reduce insulin resistance, such as metformin¹⁸ and troglitazone,²¹ on lipid metabolism.

Improvements in glycemic control during sulfonylurea therapy have been associated with decreases in plasma total cholesterol, total triglyceride, very-low-density lipoprotein (VLDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels, and either an increase or no change in HDL cholesterol levels.^14,61,62 However, some studies have demonstrated small increases²² or only small decreases^63,64 in plasma total and LDL cholesterol and triglycerides.

Metformin therapy has generally produced reductions in plasma triglyceride and total and LDL cholesterol, with little or no effect on HDL cholesterol in type 2 diabetic patients.^65-68 The favorable effect of metformin on plasma total cholesterol levels is reported to be significantly greater

(P < 0.05) than that of glyburide.^63,64 Reductions in plasma total triglyceride and total cholesterol levels appear to be a result of decreased LDL or VLDL cholesterol.⁶⁵

It has been suggested that the effect of metformin on lipids is independent of its antihyperglycemic effect.^18,68 Although the exact mechanism by which these lipid changes occur has not been determined, they may occur as a result of a direct effect of metformin on VLDL cholesterol metabolism and/or secondarily to improved insulin sensitivity.⁶⁸

Acarbose also reduces serum triglyceride concentrations but has little or no effect on total serum cholesterol concentrations. This effect appears to be mediated by suppressing the biosynthesis of VLDL cholesterol.⁵⁷ A review of more recent studies reported that fasting triglyceride levels were reduced, but only occasionally.²⁰ This effect appears to be associated with dosages >100 mg three times a day.^59,60,69,70 Of the studies that used dosages <300 mg/day, none demonstrated statistically significant changes, relative to baseline or placebo, in fasting triglyceride, total cholesterol, or cholesterol fractions.⁶⁰

Troglitazone induces increases from baseline in both LDL cholesterol (by 5–15%) and total cholesterol (by 1–8%).^54,55 In two placebo-controlled studies, the increase in LDL cholesterol was significant (P < 0.05), compared with the change seen with placebo.^54,55 However, the cholesterol/HDL and LDL/ApoB ratios were unchanged, suggesting no change in atherogenic risk. In these studies, only the 600 mg/day dosage resulted in a significant increase (P < 0.01 vs. placebo) in HDL cholesterol (by ~10–12%). However, 6- to 12-week studies failed to observe increases in HDL cholesterol during treatment with troglitazone 200–800 mg/day either alone^71,72 or in combination with a sulfonylurea.^72,73

Troglitazone reduces serum triglyceride levels, but in two monotherapy studies, only the 600 mg/day dosage produced significant reductions (P < 0.05) compared with placebo.^45,54 Serum triglycerides decreased from baseline by ~19% at the 600 mg/day dosage (P < 0.05 vs. placebo), by ~11% at the 200 and 400 mg/day dosages during monotherapy,⁵⁴ and by ~12% (P < 0.001 vs. baseline) during combination therapy with troglitazone 400 mg/day and a sulfonylurea.⁷³ At a troglitazone dosage of 800 mg/day, which is higher than the recommended maximum dose, significant (P < 0.05 vs. placebo or vs. baseline) reductions in serum triglycerides (by 14% and 32%) and significant (P < 0.05) increases in HDL cholesterol (by 16% in one study) have been observed.^54,74

Effect on Body Weight
In comparative studies of sulfonylureas and metformin, sulfonylurea therapy resulted in mean weight gains ranging from 2.6 to 5.3 kg, whereas metformin treatment was associated with either no change or a modest reduction in body weight.^{22,26,28,29,75} The stabilization or reduction in body weight noted with metformin therapy may be clinically beneficial, since the majority of type 2 diabetic patients are overweight.

Comparative and noncomparative studies have reported inconclusive findings regarding the effects of acarbose on body weight, with the majority of investigations failing to demonstrate that acarbose has an effect on body weight in either lean or obese patients.⁵⁷ In a recent trial comparing acarbose, metformin, and insulin therapy as adjunctive therapy to sulfonylurea treatment failures, body weight increased in the insulin group and decreased in both the metformin and acarbose groups. The reduction in body weight was 1.2 ± 1.9% in the metformin group and 0.6 ± 1.6% in the acarbose group. This difference was not statistically significant.⁷⁶

In clinical trials of troglitazone monotherapy, mean body weight was unchanged.^47,54 During combination therapy with troglitazone and a sulfonylurea, increases in mean body weight ranging from ~0.5 to 6 kg have occurred.^73,77

Hypoglycemia
Due to the mechanisms of action of these agents, hypoglycemia generally does not occur with metformin, acarbose, or troglitazone as sole agents.^18,21,57 Hypoglycemia with metformin⁷⁸ or troglitazone⁷⁷ is possible during concomitant use with other glucose-lowering agents, such as sulfonylureas, insulin, or ethanol.

Acarbose may increase the hypoglycemic potential of sulfonylurea therapy when used in combination.⁷⁹ Hypoglycemia occurring during acarbose therapy must be treated with glucose rather than sucrose because the mechanism of action of acarbose results in delayed gastrointestinal absorption of sucrose.

GLYCEMIC CONTROL WITH MONOTHERAPY
The sulfonylureas have been extensively used in clinical practice as first-line drug therapy in the management of type 2 diabetes, particularly in the United States, where they have, until recently, been the only oral hypoglycemic agents available.¹⁹ Although sulfonylureas vary in potency, they are similar in efficacy.¹⁴ Studies have reported decreases in basal and postprandial plasma glucose (PPPG) levels of ~3–5 mmol/L following 3–6 months of treatment with sulfonylureas.⁸⁰ Glycated hemoglobin has also been demonstrated to decrease by 20%.⁸⁰

Three double-blind, randomized, placebo-controlled clinical studies have reported significant reductions (P < 0.001) in fasting plasma glucose concentrations (FPG) (22–26% of pretreatment levels) and glycated hemoglobin levels (12–17% of pretreatment levels) with metformin monotherapy.^75,81,82 Furthermore, metformin monotherapy is comparable to sulfonylurea monotherapy in maintaining glycemic control in studies of up to 3 years’ duration.^{22,26-29,66,67,83,84}

Metformin effectively controls hyperglycemia in both lean and overweight patients and in the elderly, and its use has often led to weight reductions.^{28,29,63,66,75,85} As a result of this and its positive lipid effects, metformin may be beneficial in patients with mild to moderate hyperglycemia who are also dyslipidemic and/or prone to weight gain.

The clinical efficacy of acarbose monotherapy is more difficult to assess because of the current lack of published well-controlled studies. Most published trials to date have had small study populations (< 20 patients) and/or administered acarbose in doses exceeding 100 mg three times a day.^20,57 One large (n = 100) randomized,double-blind, placebo-controlled published study using 100 mg of acarbose 3 times daily demonstrated that the drug significantly (P < 0.05) improved glycemic control.60 Following 6 months of acarbose therapy, mean baseline PPPG, FPG, and glycosylated hemoglobin decreased by 25, 14, and 7%, respectively. Overall, there was a nonsignificant trend for acarbose to be less effective than metformin or the sulfonylureas.²⁰

Results from the majority of studies of troglitazone have been published only in abstract form. Based on reductions from baseline in fasting plasma or serum glucose and glycosylated hemoglobin, troglitazone appears to be less effective than metformin or the sulfonylureas. In a large (n = 328) double-blind study in type 2 diabetic patients, troglitazone 200–800 mg once daily for 3 months reduced fasting serum glucose by 8–13% from baseline levels.⁵⁴ There was no change from pretreatment levels in glycated hemoglobin levels with the 600 and 800 mg/day dosages, a slight increase (by 4% of pretreatment levels) with the 400 mg/day dosage, and a slight decrease (by 4%) with the 200 mg/day dosage.

The above study, however, demonstrated that troglitazone is superior to placebo. Compared with the values achieved with placebo, the values in troglitazone-treated patients (200-800 mg once daily) were significantly lower (P < 0.01) for glycated hemoglobin (by 7–13%) and fasting serum glucose levels (by 15–25%).⁵⁴ Similarly, a smaller (n = 93) double-blind, placebo-controlled study demonstrated significant (P < 0.02) reductions in FPG (by ~25%) and PPPG (by ~20%) with troglitazone 400 or 600 mg/day.⁴⁵

Results of two separate comparative studies suggest that troglitazone monotherapy may be comparable to either sulfonylurea⁴⁸ or metformin⁴⁹ monotherapy, after 12 and 3 months of therapy, respectively. However, before definite conclusions can be made regarding the efficacy of troglitazone relative to the other two agents, these results need to be confirmed in other well-controlled comparative studies.

Repaglinide’s initial doses range between 0.5 mg (naïve patients) and 2 mg before meals. The maximum dose is 4 mg before four meals. Patients should be instructed to omit the dose if the meal is to be omitted to avoid hypoglycemia. A fall of 1–2% in HbA_1c is to be anticipated. Since the drug’s effect is greatest postprandially, it should be particularly effective in those with exaggerated postprandial values. Long-term side effects, if any, have yet to be determined.^23,50

GLYCEMIC CONTROL WITH COMBINATION THERAPY
A major problem in the management of  type 2  diabetes  is that glycemic control ( e.g ., maintenance of  FPG <7.8 mmol/L [140 mg/dl] ) with diet  and/or drug treatment declines as the disease progresses. Various antidiabetic combination therapies have been established  to overcome this and should be introduced as soon as diet or drug monotherapy fail.

Oral Combinations
Metformin Plus Sulfonylureas
Metformin and sulfonylureas have different mechanisms of action that work synergistically to alleviate hyperglycemia when the two agents are used in combination. There have been consistent reports of incremental decreases in FPG levels by 20% or more when metformin was added to existing sulfonylurea therapy in patients inadequately controlled by maximum doses of the sulfonylurea.^75,86-88

Combination therapy with metformin and sulfonylureas is as effective as combined insulin/sulfonylurea therapy or insulin monotherapy in individuals presenting with treatment failure.^87,89-93 Consequently, the addition of metformin therapy may reduce the need to add insulin therapy when secondary failure with sulfonylurea drugs occurs.

Sulfonylureas Plus Acarbose
In contrast to combined therapy with metformin plus sulfonylureas, an acarbose-plus-sulfonylurea combination has an additive effect. As previously noted, data from published acarbose studies are limited by their small patient numbers (<20 patients)^94,95 Combined therapy with acarbose plus sulfonylurea has consistently resulted in substantial decreases in PPPG and FPG levels.

Metformin Plus Acarbose
Data from a 1-year randomized, double-blind, placebo-controlled study evaluating the efficacy of adding acarbose to pre-existing therapy (including diet plus metformin) showed that the addition of acarbose resulted in significant decreases (P < 0.001) in mean PPPG levels for all treatment groups except placebo.⁷⁰ The PPPG decrease for metformin recipients was 18%. There was no significant difference in FPG levels between the acarbose-plus-metformin and metformin-plus-placebo groups. This study was conducted with doses of 300 mg/day and greater.

Troglitazone Plus Sulfonylureas
Troglitazone and sulfonylureas act by different mechanisms of action and produce a synergistic lowering of hyperglycemia when used in combination. In a double-blind, placebo-controlled study in 552 type 2 diabetic patients inadequately controlled by maximum doses of glyburide (12 mg/day), dose-dependent decreases from baseline in FPG of 14, 16, and 25% were observed following 1 year of concurrent therapy with troglitazone 200, 400, and 600 mg, respectively.⁷⁷ Concurrent administration of troglitazone 400 mg/day, given in a 200 mg twice-daily regimen, produces a reduction in FPG (15%) similar to that seen with once-daily 400 mg dosing.⁷³

Metformin Plus Troglitazone
Concurrent administration of metformin (2,000 mg/day) and troglitazone (400 mg/day) demonstrated an additive antihyperglycemic effect in 28 type 2 diabetic patients with poor glycemic control at study entry (mean FPG 15.8 mmol/L [284 mg/dl]; HbA_1c 9.6%).⁴⁹ Most of these patients had secondary sulfonylurea failure. Combination therapy significantly reduced (P < 0.001) FPG (by 32–42%) and HbA_1c (by 13–16%), compared with the corresponding levels for these glycemic parameters achieved with either drug alone.

Metformin Plus Repaglinide
Moses and associates demonstrated that the combination of metformin and repaglinide was more effective than when either of the two drugs was used alone.⁵¹ Initial dosing and monitoring should be the same as when either agent is used alone.

Combinations With Insulin
In the late stages of type 2 diabetes, secondary failure to oral drug therapy often occurs, and insulin eventually becomes necessary. However, type 2 diabetic patients often have such severe insulin resistance that effective glycemic control can only be achieved with large doses of insulin.^19,96 Combining insulin with an oral antidiabetic agent is a means of improving or maintaining glycemic control while reducing exogenous insulin requirements.

Sulfonylureas Plus Insulin
Insulin has traditionally been used alone or in combination with sulfonylureas. Numerous studies have shown that combined sulfonylurea-plus-insulin therapy results in a reduction in exogenous insulin requirement, but not all studies have shown combined therapy to be superior to insulin alone in improving glycemic control.⁹⁷ However, it appears that improvements in glycemic control are achieved more consistently if insulin is added to ongoing sulfonylurea therapy at the time that secondary sulfonylurea failure occurs rather than if sulfonylurea is added to failed insulin monotherapy.⁹⁸

In two small, double-blind, placebo-controlled studies (n = 21, n = 30), combined therapy with insulin (single injection in the evening/bedtime) plus either glyburide (10 mg/day) or glipizide (40 mg/day) was significantly superior (P < 0.05) to insulin alone in improving glycemic control.^99,100 In one of these studies, 10–16 weeks of combination therapy with glyburide plus insulin led to a FPG value that was 21% lower than the FPG value with insulin alone (5.9 mmol/L [106 mg/dl] vs. 7.5 mmol/L [135 mg/dL]; P < 0.05), and a significantly greater (P < 0.05) decline from baseline in glycosylated hemoglobin absolute value (1.3 vs. 0.8%).99 Patients receiving combined therapy required one-half the mean amount of insulin as those receiving insulin alone (50 vs. 101 U with insulin alone).

In 145 obese type 2 diabetic patients with secondary sulfonylurea failure, combination therapy with glimepiride (up to 16 mg/day) plus a single dinnertime injection of 70/30 insulin was as effective as insulin monotherapy in achieving a target FPG level of 7.8 mmol/L (140 mg/dl).⁹⁸ Combination therapy resulted in earlier improvement in glycemic control and a reduction in daily insulin dosage (by 29 U), compared with insulin alone.

Combined insulin-plus-sulfonylurea therapy appears to offer no advantage over insulin alone in reducing the tendency for weight gain or risk of hypoglycemia.^98-100 In the above studies, mean weight gains were 4.9 kg with insulin plus glyburide (vs. 3.3 kg with insulin alone)99 and 2–4.5 kg with insulin plus glipizide (vs. 0.6 kg with insulin alone).¹⁰⁰ The mean frequency of hypoglycemic episodes was slightly higher with combined therapy: 8.8 with glyburide plus insulin versus 6.9 with insulin alone⁹⁹ and 0.19 per patient per week with glipizide plus insulin versus 0.09 per patient per week with insulin alone.¹⁰⁰ Weight gain and hypoglycemic episodes were reported to be equivalent with glimepiride plus insulin versus insulin alone.⁹⁸

In type 2 diabetic patients with poor glycemic control despite treatment with insulin alone, adding a sulfonylurea to the pre-existing insulin regimen improves glycemic control but may not be effective in achieving adequate glycemic control.⁹⁸

Metformin Plus Insulin
Limited data are available on the use of metformin in combination with insulin. In two double-blind, placebo-controlled studies, plasma fasting insulin levels and daily exogenous insulin requirements were reduced following the addition of metformin to the insulin regimen.^101,102 The larger of these studies 101 involved 50 obese patients with poorly controlled type 2 diabetes despite >3 months of treatment with insulin at a mean daily dose of 90 U. The addition of metformin (850 mg twice daily) resulted in a significant improvement (P < 0.05 vs. baseline and vs. placebo) in glycemic control. After 6 months of combination therapy, there were significant reductions (P < 0.05) from baseline in mean glucose profile (by 34%) and in HbA_1c (by 16%, which represents a reduction in mean absolute value of 1.9%). The addition of metformin permitted a reduction in daily insulin dose of 24% (-21.6 U). No changes in body weight occurred during combination metformin-plus-insulin therapy.

Acarbose Plus Insulin
Data from a 1-year, randomized, double-blind, placebo-controlled study of combined acarbose-plus-insulin therapy showed a 15% reduction in mean PPPG levels compared with placebo.⁷⁰ Although the reduction was statistically significant (P < 0.001), the doses of acarbose used were in the 600 mg/day range.

Troglitazone Plus Insulin
Troglitazone is approved for use in combination with insulin in the treatment of type 2 diabetes patients who require insulin. In such patients, concomitant troglitazone improves glycemic control and generally enables a reduction in the daily dose of insulin.⁷⁷ In two double-blind, placebo-controlled studies, concomitant administration of troglitazone 400 or 600 mg/day for 6 months resulted in reductions from baseline in daily insulin dose of 58% and 42%, respectively, while glycemic control was improved or maintained.⁷⁷

Some patients may be able to discontinue insulin. No reduction in insulin dose is recommended at the outset when prescribing troglitazone to poorly controlled, insulin-requiring type 2 diabetic patients. However, during concomitant troglitazone therapy, it has been recommended to decrease the dose of insulin by ~10–20% (the manufacturer recommends 10–25%), to reduce the risk of hypoglycemia when fasting and/or pre-meal glucose levels consistently drop below 6.7–7.8 mmol/L (120–140 mg/dl).¹⁰³

SIDE-EFFECT PROFILES
Sulfonylureas
Sulfonylureas are generally well tolerated. The most common and also the most serious adverse event associated with these agents is hypoglycemia.^14,16,19 Severe sulfonylurea-induced hypoglycemia occurs with an estimated incidence of 0.19–2.5 episodes per 1,000 patient-years,¹⁶ and the incidence is higher for the long-acting sulfonylureas, especially chlorpropamide (0.34/1,000 treatment-years) and glyburide (0.38/1,000 treatment-years).¹⁹ In a 3-year study, hypoglycemic reactions occurred in ~13% and 27% of patients receiving chlorpropamide and glyburide, respectively.²⁹ The most important predisposing factors for sulfonylurea-induced hypoglycemia are increasing age and impaired renal function.^104,105

Other side effects with sulfonylurea therapy are rare and include dermatological hypersensitivity, gastrointestinal discomfort, and vasomotor symptoms (most frequently reported with chlorpropamide).¹⁹

Metformin
The most common adverse effects of metformin are gastrointestinal symptoms,^16,18,52 which may be relieved by dosage reduction and rarely require discontinuation of treatment.^52,106 During long-term metformin administration, only 4.2% of patients discontinued therapy because of gastrointestinal side effects.⁸⁶

Malabsorption of vitamin B12 and decreased folate absorption have been infrequently reported with long-term metformin therapy. Although there are no clinical manifestations of these effects, annual serum B12 measurements are recommended.^16,18,52,78 These decreases are rapidly reversible with vitamin B12 supplementation or discontinuation of metformin therapy. Only three cases of megaloblastic anemia have been reported in the literature with metformin therapy.^107-109

Lactic acidosis, a serious and potentially lethal metabolic condition, has occurred with all biguanides, but rarely with metformin. The mean incidence of lactic acidosis associated with metformin therapy is only about 0.03 cases per 1,000 patient-years.^18,104 Strict observance of contraindications and prescribing precautions substantially reduces this risk.^16,78

Data from a retrospective study conducted in Sweden from 1977 to 1991 indicate that the reported incidence of metformin-associated lactic acidosis is low and is decreasing.¹¹⁰ The incidence of lactic acidosis is lower than that of the equally serious sulfonylurea-induced hypoglycemia. A retrospective comparative risk study in Sweden reported that, between 1972 and mid-1981, the incidence of glyburide-induced hypoglycemic coma (0.19 per 1,000 patient-years of use) was significantly (P = 0.036) greater than the incidence of metformin-associated lactic acidosis (0.08 per 1,000 patient-years of use).¹⁰⁵ The risk of mortality from metformin-induced lactic acidosis is slightly lower than the mortality risk from glyburide-induced hypoglycemia (0.24 per 1,000 patient-years vs. 0.33 per 1,000 patient years, respectively).^105,111

Acarbose
The most common adverse events associated with acarbose therapy are gastrointestinal disturbances, most frequently abdominal pain, diarrhea, and flatulence.⁵⁷ These events arise from the drug’s mechanism of action and are related to the presence of undigested carbohydrate in the lower gastrointestinal tract. Several studies have demonstrated that these adverse events decrease as the duration of acarbose therapy increases. Moreover, the severity of the gastrointestinal disturbances may be reduced by decreasing the dose of medication and by good dietary habits.^20,57

Elevations in serum transaminase levels may occur during acarbose therapy. In studies of up to 12 months’ duration, treatment-emergent elevations of serum transaminases occurred in 15% of acarbose recipients compared with 7% of placebo recipients.⁷⁹ These elevations appear to be dose-related and are asymptomatic, reversible, more common in women, and in general not associated with other evidence of liver dysfunction.⁷⁹

Troglitazone
Troglitazone is generally well tolerated.⁷⁷ The most serious adverse event reported with short- and long-term troglitazone therapy is idiosyncratic hepatocellular injury, although the incidence is rare. In most cases, hepatocellular injury manifested as reversible jaundice but led to hepatic failure or death in a few cases. Therefore, serum transaminase levels should be monitored at frequent intervals, especially during the first year of treatment and at the first signs of hepatic dysfunction (e.g., dark urine, fatigue, gastrointestinal disturbances). Troglitazone should be discontinued in patients developing jaundice or ALT levels >3 times the upper limit of normal.⁷⁷

CONCLUSION
Oral antidiabetic compounds have an established role in the treatment of type 2 diabetes. Metformin is as effective as the sulfonylureas and superior to acarbose in controlling plasma glucose levels in patients with type 2 diabetes. Unconfirmed data suggest that troglitazone may be as effective as sulfonylureas and metformin. No conclusions can be drawn until further comparative data are available.

While the sulfonylureas, metformin, and troglitazone can cause serious adverse events, their incidences are low and can be minimized by strict adherence to the prescribing guidelines and close monitoring of treated patients.

Metformin has some advantages over sulfonylureas and acarbose, including the stabilization of body weight in patients in whom weight gain is a concern and the reduction of plasma lipid levels in individuals with hyperlipidemia. Troglitazone shares the weight advantage with metformin, but the two agents differ in their lipid effects. Total and LDL cholesterol are reduced by metformin but elevated by troglitazone; both agents reduce serum triglycerides.

Combination therapy using two antihyperglycemic agents with different but complementary mechanisms of action may improve glycemic control in patients with type 2 diabetes inadequately controlled by either agent alone. Both metformin and troglitazone are approved for use in combination with a sulfonylurea when failure of sulfonylurea monotherapy occurs.

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Charles M. Clark Jr., MD, is the director of the Diabetes Research and Training Center at the Indiana University Medical School Regenstrief Health Institute in Indianapolis, Ind.

Note of disclosure: Dr. Clark has received honoraria and research support from and has served on advisory committees for Eli Lilly, Bristol-Myers Squibb, Hoescht Marion Roussel, and Bayer Corporation, all of which manufacture and market pharmaceutical products for the treatment of diabetes.

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