Volume 11 Number 4, 1998, Pages 211-221
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Oral Therapy in Type 2 Diabetes:
Charles M. Clark Jr., MD
Type 2 diabetes (non-insulin-dependent diabetes mellitus) is a metabolic disorder whose etiology and pathogenesis are not completely understood,1 yet it constitutes 92% of cases of diabetes in the United States. The two primary pathogenic factors leading to type 2 diabetes are insulin resistance and decreased insulin secretion, which arise from abnormalities within the liver, skeletal muscle, and pancreatic -cells.
The extent of these defects varies among type 2 diabetic patients. Impaired insulin sensitivity occurs at the tissue (liver and skeletal muscle) level, and it is a predominant finding in overweight diabetic patients. Impaired insulin secretion occurs at the level of the pancreatic -cell and occurs primarily in lean diabetic individuals.2 Although large-scale studies have yet to confirm which of these abnormalities prevails, recent studies in small patient populations suggest that insulin resistance may be the primary defect,3,4 but that a defect in insulin secretion is a prerequisite for progression to type 2 diabetes.2
Insulin resistance is characterized by decreased uptake and metabolism of glucose in skeletal muscle3-5 and by hepatic overproduction of glucose. Patients with insulin resistance have significant hyperglycemia, even though their plasma insulin levels may be normal or increased.
The hyperinsulinemia that occurs in these patients is compensatory, as the pancreatic -cells attempt to reduce hyperglycemia.3,5 Hyperinsulinemia also reflects impaired insulin sensitivity and may result from defects at the level of the insulin receptor, in messenger signals, or in the glucose transporter system.3,4
Moreover, insulin resistance is associated with several atherogenic abnormalities that increase the risk of coronary heart disease (CHD).6-10 These include increased plasma triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol levels, and hypertension. The combination of insulin resistance and its associated atherogenic risk factors has been referred to as "Syndrome X."6-11
The second pathogenic factor, defective insulin secretion, is believed to contribute to the development of overt type 2 diabetes, particularly fasting hyperglycemia. Although fasting plasma insulin is frequently increased in patients with type 2 diabetes, insulin secretory defects in the pancreatic -cell are also present. These defects appear to occur early in the course of the disease; in the majority of individuals there is a loss of first-phase insulin response to an intravenous glucose challenge. Therefore, defects in both insulin resistance and insulin secretion contribute to the etiology of type 2 diabetes.3,4
As the disease progresses and hyperglycemia worsens, pancreatic -cells no longer adequately respond to the glycemic stimulus, and insulin secretion declines. This combination of effects results in chronic hyperglycemia, which further impairs insulin secretion and action.2,3,12,13 This concept of chronic increments in plasma glucose levels leading to progressive impairment of insulin secretion is referred to as "glucose toxicity" and is an important aspect of type 2 diabetes treatment.2,3
Because type 2 diabetes is frequently associated with hyperglycemia-induced long-term complications, hypertension, obesity, and lipid abnormalities, early detection and management of type 2 diabetes is important. The primary treatment objective in the management of type 2 diabetes is to achieve and maintain good glycemic control. Controlling co-existing conditions, detecting and treating chronic complications (e.g., retinopathy and neuropathy), and avoiding hypoglycemia are secondary objectives.8,14,15 Table 1 summarizes targets for metabolic control and body mass index in type 2 diabetic patients.16 In overweight individuals, these abnormalities improve with weight reduction and exercise. Only when this approach has been ineffective should drug therapy be initiated.17
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.
Hepatic Glucose Production (HGP)
Peripheral Glucose Utilization
Other Antihyperglycemic Effects
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 does not appear to have a direct effect on insulin resistance or on insulin-stimulated glucose uptake in humans.20
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 612 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.
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 A1c were seen. A lowering of HbA1c 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 HbA1c 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
Troglitazone generally reduces fasting 45,47,54,55 and postprandial46plasma insulin levels. Reductions from baseline in plasma insulin levels of 531% 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
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 decreases63,64 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 515%) and total cholesterol (by 18%).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 ~1012%). However, 6- to 12-week studies failed to observe increases in HDL cholesterol during treatment with troglitazone 200800 mg/day either alone71,72 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
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
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
Three double-blind, randomized, placebo-controlled clinical studies have reported significant reductions (P < 0.001) in fasting plasma glucose concentrations (FPG) (2226% of pretreatment levels) and glycated hemoglobin levels (1217% 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 200800 mg once daily for 3 months reduced fasting serum glucose by 813% 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 713%) and fasting serum glucose levels (by 1525%).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.
Repaglinides initial doses range between 0.5 mg (na´ve 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 12% in HbA1c is to be anticipated. Since the drugs 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
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
Metformin Plus Acarbose
Troglitazone Plus Sulfonylureas
Metformin Plus Troglitazone
Metformin Plus Repaglinide
Combinations With Insulin
Sulfonylureas Plus Insulin
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, 1016 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 24.5 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
Acarbose Plus Insulin
Troglitazone Plus Insulin
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 ~1020% (the manufacturer recommends 1025%), to reduce the risk of hypoglycemia when fasting and/or pre-meal glucose levels consistently drop below 6.77.8 mmol/L (120140 mg/dl).103
Other side effects with sulfonylurea therapy are rare and include dermatological hypersensitivity, gastrointestinal discomfort, and vasomotor symptoms (most frequently reported with chlorpropamide).19
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
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
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.
Copyright ę 1998 American Diabetes Association
Last updated: 11/98