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| ORAL PHARMACOLOGICAL AGENTS FOR TYPE 2 DIABETES:
SULFONYLUREAS, MEGLITINIDES, METFORMIN, THIAZOLIDINEDIONES, a-GLUCOSIDASE
INHIBITORS, AND EMERGING APPROACHES Chapter 14 - Joseph L. Evans, Ph.D. and Robert J. Rushakoff, M.D. August 26, 2002 |
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INTRODUCTION The prevalence of type 2 diabetes has reached epidemic proportions in the US and worldwide, and is projected to increase dramatically (1). Furthermore, the prevalence of insulin resistance, a major causative factor in the early development of type 2 diabetes and an independent risk factor for cardiovascular disease and the metabolic syndrome X, is even more widespread (2-4). Since dietary modification and increased physical activity provide insufficient glucose control over the long-term course of the disease, the vast majority of patients require some type of pharmacological intervention (5). In response to the enormity of the growing problem, efforts to identify and develop new pharmacological agents for type 2 diabetes have increased dramatically in recent years. These efforts have resulted recently in the successful introduction of several new treatment options, and additional new therapies will likely gain approval in the US within a few years. Currently, there are five classes of oral pharmacological agents available to treat type 2 diabetes: sulfonylureas, meglitinides, metformin (a biguanide), thiazolidinediones, and a-glucosidase inhibitors (Figure 1; Table 1, see below). The actions of sulfonylureas and meglitinides involve the stimulation of insulin secretion; metformin suppresses hepatic glucose production; the thiazolidinedione class targets peripheral tissue insulin resistance; and the a-glucosidase inhibitors inhibit complex carbohydrate breakdown in the gut. A summary of their primary sites of action is given in Figure 2. There are no studies directly comparing the efficacy of all the oral agents. Data from multiple studies are provided in Tables 2 and 3 (see below), which summarize comparative efficacies when these drugs are used as monotherapy and in combination. A cost comparison of the medications is given in Table 4 (see below). Since several recent comprehensive reviews have focused on this topic (6-11), the overall objective of this chapter is to provide a concise, comparative overview of the available oral treatments, and to highlight some emerging approaches.
Sulfonylureas, derived from sulfonic acid and urea, were initially developed in the 1950's and have remained a cornerstone of therapy for type 2 diabetes (6). The combination of their proven efficacy in most patients, low incidence of adverse events, and low cost has contributed to their success and continued use. They are frequently classified as either 1st generation or 2nd generation agents. First generation sulfonylureas (acetohexomide, chlorpropamide, tolazamide, and tolbutamide) possess a lower binding affinity for the ATP-sensitive potassium channel, their molecular target (vide infra), and thus require higher doses to achieve efficacy, increasing the potential for adverse events. In addition, the plasma half-life of 1st generation sulfonylureas is extended (e.g. 5-36 h) compared to the 2nd generation agents. Chlorpropamide was once the most commonly used oral agent, but now it is rarely prescribed. Unique complications associated with chlorpropamide are hyponatremia (SIADH) and an alcohol flushing reaction (disulfiram-Antibuse reaction). In addition, tolbutamide, acetohexamide and tolazamide generally require 2 or 3 doses per day and are rarely used. More recently, 2nd generation sulfonylureas including glyburide (glibenclamide; (Figure 1.1), glipizide (Figure 1.2), and glimepiride (Figure 1.3) were introduced, and are now widely used. The 2nd generation sulfonylureas are much more potent compounds (~ 100-fold), possess a more rapid onset of action, and generally have shorter plasma half-lives and longer duration of action compared to the 1st generation agents. Sulfonylureas are insulin secretogogues, since they control blood glucose levels by directly stimulating first-phase insulin secretion in the pancreatic beta cells. Through the concerted efforts of GLUT2 (the high Km glucose transporter) (12), glucokinase (the glucose sensor) (13), and glucose metabolism, these cells are responsible for sensing and secreting the appropriate amount of insulin in response to a glucose stimulus (14). Mitochondrial glucose metabolism leads to ATP generation and increases the intracellular ratio of ATP/ADP, which results in the closure of the ATP-sensitive potassium channel (KATP; a 140 kDa membrane protein) on the plasma membrane. Closure of this channel depolarizes the membrane and triggers the opening of voltage-sensitive calcium channels, leading to the rapid influx of calcium. Increased intracellular calcium causes an alteration in the cytoskeleton, and stimulates translocation of insulin-containing secretory granules to the plasma membrane and the exocytotic release of insulin. The KATP channel is comprised of two subunits, both of which are required for the channel to be functional. One subunit contains the cytoplasmic binding sites for both sulfonylureas and ATP, and is designated as the sulfonylurea receptor type 1 (SUR1). The other subunit is the potassium channel, which acts as the pore-forming subunit (15). Either an increase in the ATP/ADP ratio or ligand binding (by sulfonylureas, meglitinides) to SUR1 results in the closure of the KATP channel and insulin secretion. Studies comparing sulfonylureas and non-sulfonylurea insulin secretogogues have identified several distinct binding sites on the SUR1 that cause channel closure. Some sites exhibit high affinity for glyburide and other sulfonylureas, while other sites exhibit high affinity for the non-sulfonylurea secretogogues (vide infra). The over clinical efficacy of sulfonylureas in patients with type 2 diabetes is related to the pre-treatment levels of fasting plasma glucose and HbA1C. The higher the fasting glucose level, the greater the effect will be. In patients with a pre-treatment glucose level of approximately 200 mg/dl (11.1 mmol/l), sulfonylureas typically will reduce glucose by 60-70 mg/dl (3.3-3.9 mmol/l) and HbA1C by 1.5-2% (Table 2). The most responsive patients are those who exhibit mild-to-moderate fasting hyperglycemia (<200-240 mg/dl; <12.2-13.3 mmol/l), along with adequate residual b-cell function (evidenced by elevated fasting C-peptide). When used at maximally effective doses, results from well-controlled clinical trials have not indicated a superiority of one 2nd generation sulfonylurea over another. Similarly, 2nd generation sulfonylureas exhibit similar clinical efficacy compared to the 1st generation agents. The principal advantage of glimepiride and glipizide compared to other agents is the once daily dosing regimen. Approximately 10-20% of patients will exhibit a poor initial response to sulfonylureas (primary failures). While these patients are typically those who have severe fasting hyperglycemia (>280 mg/dl; >15.5 mmol/l) and reduced fasting C-peptide levels, these tests are not specific enough to help decide on the usefulness of a sulfonylurea for an individual patient. In addition, treatment with sulfonylureas results in the eventual loss of therapeutic effectiveness (secondary failure) in the range of 3-10% per year (6). The major side effect from sulfonylurea treatment is hypoglycemia. This side effect is really just an extension of the therapeutic objective. Mild hypoglycemic events occur in approximately 2-4% of patients and severe hypoglycemic reactions that require hospitalization occur at a frequency of 0.2-0.4 cases per 1000 patient-years of treatment (16). In light of this, initiation of treatment with sulfonylureas should be at the lowest recommended dose. An additional undesirable effect of sulfonylurea therapy (as is also the case with insulin therapy) is weight gain. In the UKPDS, sulfonylurea treatment caused a net weight gain of 3 kg, which occurred during the first 3-4 years of treatment and then stabilized (17). In contrast, weight gain in response to insulin therapy increased progressively for the duration of the study. As mentioned above, chlorpropamide is associated with hyponatremia (SIADH) and an alcohol flushing reaction (disulfiram-Antibuse reaction). All the agents can cause intrahepatic cholestasis. Rarely maculopapular or urticarial rashes occur. In renal failure, the dose of the sulfonylurea agent will require adjustment based on glucose monitoring. The half-life of insulin is extended in renal failure and thus there is an increased risk for hypoglycemia. This risk is typically manifest with fasting hypoglycemia. MEGLITINIDES: REPAGLINIDE AND NATEGLINIDE The meglitinides are a novel class of non-sulfonylurea insulin secretogogues characterized by a very rapid onset and abbreviated duration of action. Repaglinide, a benzoic acid derivative introduced in 1998, was the first member of the meglitinide class. Nateglinide is a derivative of the amino acid D-phenylalanine and was introduced to the market in 2001. Unlike sulfonylureas, repaglinide and nateglinide stimulate first-phase insulin release in a glucose-sensitive manner, theoretically reducing the risk of hypoglycemic events. The delivery of insulin as an early, transient 'burst' at the initiation of a meal affords several major physiological benefits (reviewed in (18,19)). These include rapidly suppressing hepatic glucose production and reducing the stimulus for additional insulin that would be required subsequently to dispose of a larger glucose load. Thus, the rapid onset/short duration stimulation of insulin release by meglitinides should enhance control of prandial hyperglycemia, while reducing the risk for post-absorptive hypoglycemia and limiting exposure to hyperinsulinemia. Similar to sulfonylureas, meglitinides are insulin secretogogues, since they control blood glucose levels by directly stimulating first-phase insulin secretion in the pancreatic beta cells. Receptor-binding studies performed in betaTC-3 cells identified a high-affinity repaglinide (KD = 3.6 nmol/l) site having lower affinity for glyburide (14.4 nmol/l), and one high-affinity glyburide (25 nmol/l) site having lower affinity for repaglinide (550 nmol/l)(Figure 1.4)(20). Repaglinide is approximately 5 times more potent than glyburide in stimulating insulin secretion. Unlike glyburide (and other sulfonylureas), repaglinide does not stimulate insulin secretion in vitro in the absence of glucose. Rather, it enhances glucose-stimulated insulin secretion especially at 180 mg/dl (10 mmol/l) glucose. The mechanism of action of nateglinide (Figure 1.5) also involves the binding to and closure of the KATP channel resulting in membrane depolarization, an influx of calcium, and insulin exocytosis (21). The kinetics of interaction of nateglinide with the KATP channel are distinct compared to both repaglinideand sulfonylureas, and accounts for its rapid insulinotropic effects. The onset of action of nateglinide is similar to that of glyburide but three-fold more rapid than that of repaglinide (18). When nateglinide is removed from the KATP channel, its effect is reversed twice as quickly as glyburide and five times more quickly than repaglinide. Thus, nateglinide initiates a more rapid release of insulin that is shorter in duration compared to repaglinide(18), despite having an in vivo pharmacokinetic profile that is similar (22,23). The efficacy of repaglinide, when used as a monotherapy, is similar to sulfonylureas (24). Repaglinide treatment of patients with type 2 diabetes reduced fasting plasma glucose by approximately 60 mg/dl and HbA1C by 1.7% (25). In a double-blind placebo-controlled study, repaglinide had similar effects on lowering HbA1C (0.5-2%) and fasting plasma glucose (65-75 mg/dl; 3.6-4.2 mmol/l) compared to glyburide (26). Repaglinide is also efficacious when used in combination with either metformin or troglitazone (a thiazolidinedione withdrawn from the market). In patients treated with repaglinide and metformin, HbA1C was decreased from 8.3% to 6.9% and fasting plasma glucose by 40 mg/dl (2.2 mmol/l) (27). Although lowered, the changes observed in subjects treated with either repaglinide or metformin monotherapy were not significant for HbA1C (0.4 and 0.3% decrease, respectively), or fasting plasma glucose (9 mg/dl (0.5 mmol/l) increase and 5.4 mg/dl (0.3 mmol/l) decrease, respectively). Significant increases in body weight occurred in the both repaglinide and combined therapy groups (2.4 ± 0.5 and 3.0 ± 0.5 kg, respectively). The combination therapy of repaglinide and troglitazone showed a significant reduction in mean HbA1C values (1.7%) that was greater than with either type of monotherapy (28). Repaglinide monotherapy resulted in a reduction of HbA1C values that was significantly greater than troglitazone (0.8% vs. 0.4%). In addition, combination therapy was more effective in reducing fasting plasma glucose (80 mg/dl) than either repaglinide (43 mg/dl) or troglitazone (46 mg/dl) monotherapies. Repaglinide is also efficacious when used in combination with other available thiazolidinediones, rosiglitazone and pioglitazone (29). The efficacy of nateglinide when used as a monotherapy is similar to sulfonylureas and repaglinide (19,30). However, several therapeutically attractive features distinguish nateglinide from repaglinide and sulfonylureas. Nateglinide produces a more rapid post-prandial increase in insulin secretion, and its duration of response is shorter than that of glyburide (31,32). Thus, the risk of post-absorptive hypoglycemia should be lower than with either sulfonylureas or repaglinide. The efficacy of nateglinide treatment has been evaluated alone and in combination with metformin in patients with type 2 diabetes (33). In this randomized double-blind study, patients with an HbA1C level between 6.8 and 11.0% during a 4-week placebo run-in received 24 weeks' treatment with 120 mg nateglinide before meals (n = 179), 500 mg metformin three times a day (n = 178), combination therapy (n = 172), or placebo (n = 172). At the study conclusion, HbA1C and fasting plasma glucose were significantly reduced from baseline with nateglinide [0.5% and 12.6 mg/dl (0.7 mmol/l), respectively] and metformin [0.8% and 28.8 mg/dl (1.6 mmol/l), respectively], but was increased with placebo [0.5% and 7.2 mg/dl (0.4 mmol/l), respectively]. Combination therapy was additive [HbA1C, 1.4% and glucose, 43.2 mg/dl (2.4 mmol/l)]. Although only preliminary data are available, nateglinide also appears effective when used in combination with thiazolidinediones (19,29). In 1-year trials, the most common adverse events reported in repaglinide recipients (n = 1,228) were hypoglycemia (16%), upper respiratory tract infection (10%), rhinitis (7%), bronchitis (6%) and headache (9%). The overall incidence of hypoglycemia was similar to that recorded in patients receiving glibenclamide, glipizide or gliclazide (18%; n = 597); however, the incidence of serious hypoglycemia appears to be slightly higher in sulphonylurea recipients. Weight gain does occur in patients treated with repaglinide, but the magnitude is significantly less compared to treatment with glyburide. In patients switched from sulfonylureas to repaglinide, no weight gain was observed; in drug-naïve patients, repaglinide-treatment increased body weight by approximately 3% (6lb) (26,34). The clinical trials of nateglinide carried out to date have found the drug to be safe and well tolerated. Dosage regimens ranging from 60 to 240 mg have been evaluated. The most common adverse effects are nausea, diarrhea, dizziness, and lightheadedness. The incidence of mild hypoglycemia is lower with nateglinide than for repaglinide and no reports of severe hypoglycemia, consistent with the mechanism of action of nateglinide. In the clinical studies carried out to date, there have been no reports of any increase body weight gain. Metformin (dimethlybiguanide) is a synthetic analog of the natural product guanidine, whose history as a treatment for diabetes can be traced to medieval times (35). Metformin has surpassed the sulfonylureas as the most prescribed oral agent for type 2 diabetes in the US. In the major European markets, metformin is the second most prescribed agent after glyburide (36). The widespread acceptance of metformin evolved after the realization that lactic acidosis was not a major problem in individuals with normal renal function. Phenformin, a structurally similar analog of metformin, was previously withdrawn from the market in many countries due its propensity to induce lactic acidosis. Metformin is recommended as a first-line therapy in newly diagnosed individuals, and can be used in combination with an insulin secretagogue (sulfonylurea or meglitinide), thiazolidinedione, a-glucosidase inhibitor, or insulin (16,37). When used as a monotherapy, metformin decreases HbA1C by 1.5-2.0%, increases insulin sensitivity, does not promote weight gain, and has an acceptable side effect profile. An elevated rate of basal hepatic glucose output is the primary determinant of elevated fasting blood glucose levels in patients with type 2 diabetes (38). The primary effect of metformin (Figure 1.6) is the suppression of basal hepatic glucose production, thereby reducing fasting plasma glucose (36,39,40). Despite the large number of studies both in vitro and in humans that have established this mode of action, the molecular target of metformin action still awaits identification. Metformin does not stimulate insulin secretion; in contrast, metformin reduces fasting plasma insulin and improves whole-body insulin-stimulated glucose metabolism (insulin sensitivity) (36,40). While it is possible that the beneficial effect of metformin on insulin sensitivity is mediated directly, a more likely explanation is that it is secondary to a reduction in hyperglycemia, triglycerides, and free fatty acids. Recent in vitro and in vivo evidence has shown that metformin activates the AMP-activated protein kinase (AMPK) (41), a major cellular regulator of lipid and glucose metabolism (42). As a result, acetyl-CoA carboxylase activity was reduced, fatty acid oxidation induced (due to decreased malonyl-CoA), and the expression of lipogenic enzymes along with SREBP-1, a key lipogenic transcription factor, suppressed (41). The use of a novel AMPK inhibitor indicated that AMPK activation was required for the inhibitory effect of metformin on glucose production in hepatocytes. In isolated rat skeletal muscles, metformin stimulated glucose uptake coincident with AMPK activation. These results are intriguing in that they implicate the activation of AMPK as a unified explanation for the beneficial effects of metformin. A large number of well-controlled clinical studies have established that metformin monotherapy consistently reduces fasting plasma glucose by 60-70 mg/dl (3.3-3.9 mmol/l) and HbA1C by 1.5-2.0% (8,37,40). Thus, the efficacy of metformin is in the same range as that observed for monotherapy treatment with sulfonylureas. Similar to the sulfonylurea treatment, the overall magnitude of response to metformin is directly related to the starting fasting plasma glucose concentration. Metformin also reduces fasting plasma insulin, triglycerides, and free fatty acids (40). Unlike sulfonylurea treatment, metformin monotherapy is not associated with weight gain and even promotes a modest weight loss. When used in combination with other oral agents or insulin, weight gain is not observed. Metformin is the only oral agent that when used as a monotherapy has been reported to reduce the risk of developing macrovascular complications (43). In patients with type 2 diabetes in the US, the mean HbA1C is approximately 10% and fasting plasma glucose approximately 200-240 mg/dl (40). In patients of this sort, monotherapy with either metformin or a sulfonylurea generally will decrease plasma glucose to <140 mg/dl (<7.8 mmol/l) in about 25-30% of patients. In contrast, combined metformin and sulfonylurea therapy increases the percentage of patients who achieve this level of control to approximately 60-70% (40). When added to a sulfonylurea, the effects of both agents are additive, consistent with their different mechanisms of action. Interestingly, in patients that no longer responded to sulfonylurea treatment (secondary failures) and were removed from treatment, addition of metformin had minimal effects (44). Thus, in these patients, sulfonylurea treatment was still eliciting an effect, emphasizing the need to continue treatment with both agents. The additive effect of metformin and sulfonylurea therapy is illustrated in Figure 3. As shown, there was no change in glucose levels when the sulfonylurea was changed to metformin. However, when the metformin was added, there was a dramatic decrease in plasma glucose. In fact, this pattern is seen in virtually all studies comparing two oral agents. This concept is illustrated in Figure 4. When a patient is on drug A and they are changed to drug B, no improvement in glucose control will be seen. However, if drug B is added to drug A, there is an improvement. This concept can often be extended by the addition of drug C, drug D, etc.
Side Effects and Contraindications The most common side effects of metformin are gastrointestinal disturbances (abdominal discomfort, diarrhea), which occur in approximately 20-30% of patients. These effects are generally transient, and can be minimized or avoided by careful dose titration. The incidence of lactic acidosis is rare and occurs with a frequency of 3 cases per 100,000 patient-years. However, metformin is contraindicated in patients with impaired renal function and liver disease. The risk of lactic acidosis can be minimized when the following are considered:
THIAZOLIDINEDIONES: PIOGLITAZONE AND ROSIGLITAZONE Pioglitazone and rosiglitazone are members of the thiazolidinedione class of insulin sensitizing compounds originally discovered and characterized for their glucose- and lipid-lowering activity (45,46). These compounds decrease insulin resistance and enhance the biological response to endogenously produced insulin, as well as insulin administered by injection (9,47,48). Each drug is approved for use in the US as monotherapy, which results in a significant reduction in fasting plasma glucose by 60-80 mg/dl and in HbA1C by 1.4-2.6% (9). In addition, pioglitazone is approved for use in combination with insulin, metformin, or a sulfonylurea, and rosiglitazone is approved for use in combination with metformin or a sulfonylurea. Neither drug is approved in the US for use in combination with a sulfonylurea and metformin. Troglitazone , another member of this chemical class, was withdrawn from US, European, and Japanese markets in 2000 due to idiosyncratic hepatic reaction leading to hepatic failure and death in some patients. Although there are some data from animal studies suggesting that hepatic toxicity might be characteristic of the thiazolidinedione class (49), current clinical evidence indicates that pioglitazone and rosiglitazone treatment do not result in liver toxicity (47,50-52). The primary effects of pioglitazone (Figure 1.7) and rosiglitazone (Figure 1.8) are the reduction of insulin resistance and improvement of insulin sensitivity, resulting in a reduction of fasting plasma glucose, insulin, and free fatty acids (9,53-56). Unlike other existing anti-diabetic medications that possess a very rapid onset of activity, pioglitazone and rosiglitazone exhibit a characteristic delay from 4-12 weeks in the onset of their therapeutic benefits. This is likely related to their mode of action, which involves the regulation of gene expression (53,57,58). Pioglitazone and rosiglitazone are selective agonists for the peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the superfamily of nuclear hormone receptors that function as ligand-activated transcription factors (59,60). The PPAR family, which also includes PPARalpha and PPARdelta, functions as receptors for fatty acids and their metabolites (e.g. eiconasoids) and, consequently, plays a critical physiological role the regulation of glucose, fatty acid, and cholesterol metabolism. PPARalpha is the receptor for the fibrate class of lipid-lowering drugs, and PPARdelta is involved in the regulation of high-density lipoprotein metabolism (60,61). The structure-activity relationship between PPARgamma agonists and their glucose lowering activity in vivo has been established (62). In the absence of ligand, PPARs bind as heterodimers with the 9-cis retinoic acid receptor (RXR) and a multi-component co-repressor complex to a specific response element (PPRE) within the promoter region of their target genes (60,63). Once PPAR is activated by ligand, the co-repressor complex dissociates allowing the PPAR-RXR heterodimer to associate with a multi-component co-activator complex resulting in an increased rate of gene transcription. The target genes of PPARgamma include those involved in the regulation of lipid and carbohydrate metabolism (64-66). It does not appear that rosiglitazone and pioglitazone improve insulin sensitivity and glucose disposal by direct effects on either liver or muscle. PPARgamma is expressed chiefly in adipose tissue, and its expression in liver and skeletal muscle is low (67,68). Thus, it is more likely that the primary effects of these drugs are on adipose tissue, followed by secondary benefits on other target tissues of insulin (69). The ability of rosiglitazone and pioglitazone to decrease circulating free fatty acids could lead to an improvement in insulin action in the periphery (53,54,70,71). More recently, PPARgamma agonists have been reported to increase the expression and circulating level of adiponectin (Acrp30), an adipocyte-derived protein with insulin sensitizing activity (72,73), in diabetic rodents (69) and in patients with type 2 diabetes (74). Recognition of the importance of PPARgamma in the overall regulation of carbohydrate and lipid metabolism along with growing realization that the adipocyte is an endocrine organ (75,76) suggests that investigations in this area will intensify, and perhaps uncover additional mechanisms by which rosiglitazone and pioglitazone improve insulin sensitivity and glucose disposal. Rosiglitazone The clinical efficacy of rosiglitazone and pioglitazone therapy has been reviewed recently (9,47,51,77-81). Two 26-week, double blind, placebo-controlled clinical studies have established that rosiglitazone monotherapy reduces fasting plasma glucose and HbA1C in patients with type 2 diabetes (82,83). Treatment with rosiglitazone at 4 mg/day reduced fasting plasma glucose by approximately 30-45 mg/dl and HbA1C by 0.8-1.0%, compared with placebo. Treatment with rosiglitazone at 8 mg/day reduced fasting plasma glucose by approximately 45-65 mg/dl and HbA1C by 1.1-1.5%, compared with placebo (9,47,77). In patients with type 2 diabetes inadequately controlled with metformin, rosiglitazone produced a significant reduction in HbA1C compared to metformin treatment alone (84,85). In another study in which rosiglitazone was directly compared to a maximum stable dose of glyburide (15 mg/day), rosiglitazone reduced fasting plasma glucose by 25 mg/dl at 4 mg/day, and 40 mg/dl at 8 mg/day (77). The reduction in HbA1C was 0.7% for glyburide, 0.3% for rosiglitazone at 4 mg/day, and 0.5% for rosiglitazone at 8 mg/day. Pioglitazone Double blind, placebo-controlled studies with pioglitazone as monotherapy, have established that this agent reduces fasting plasma glucose HbA1C in patients with type 2 diabetes (51,78,81,86). Patients treated with 15, 30, or 45 mg (once daily) pioglitazone had significant mean decreases in HbA1C (range -1.00 to -1.60% difference from placebo) and fasting plasma glucose (-39.1 to -65.3 mg/dl difference from placebo). The decreases in fasting plasma glucose were observed as early as the second week of therapy; maximal decreases occurred after 10-14 weeks and were maintained until the end of therapy (week 26). There was no evidence of drug-induced hepatotoxicity, or elevated alanine aminotransferase activity. The efficacy and tolerability of pioglitazone in combination with metformin has been assessed in patients with type 2 diabetes mellitus (87). Patients receiving pioglitazone (30 mg) + metformin had statistically significant mean decreases in HbA1C (-0.83%) and fasting plasma glucose levels (-37.7 mg/dl) compared with placebo + metformin. Decreases in fasting plasma glucose levels occurred as early as the fourth week of therapy, the first time point at which fasting plasma glucose was measured. The pioglitazone + metformin group had significant mean percentage changes in levels of triglycerides (-18.2%) and high-density lipoprotein cholesterol (+8.7%) compared with placebo + metformin. Mean percentage increases were noted in low-density lipoprotein cholesterol levels (7.7%, pioglitazone + metformin; 11.9%, placebo + metformin) and total cholesterol (4.1%, pioglitazone + metformin; 1.1%, placebo + metformin), with no significant differences between groups. In the extension study, patients treated with open-label pioglitazone + metformin for 72 weeks had mean changes from baseline of -1.36% in HbA1C and -63.0 mg/dl in fasting plasma glucose. In this study, there was no evidence of drug-induced hepatotoxicity. The efficacy and tolerability of pioglitazone in combination with a sulfonylurea has been also assessed in patients with type 2 diabetes mellitus (88). Patients receiving pioglitazone + sulfonylurea had significant decreases from baseline in HbA1C and fasting plasma glucose levels compared with patients treated with placebo + sulfonylurea. As compared with placebo, HbA1C decreased by 0.9% with 15 mg/day pioglitazone, and 1.3% with 30 mg pioglitazone; fasting plasma glucose levels decreased by 39 mg/dl with 15 mg pioglitazone, and by 58 mg/dl with 30 mg pioglitazone. Both pioglitazone + sulfonylurea groups had significant mean percent decreases in triglyceride levels (17% for 15 mg; 26% for 30 mg), and increases in high-density lipoprotein cholesterol levels (6% for 15 mg; 13% for 30 mg) compared with placebo + sulfonylurea. Pioglitazone was well tolerated in this study. The effect of pioglitazone on whole-body insulin action in patients with type 2 diabetes has been studied extensively by Miyazaki et al. (55,89) and others (56). Twenty-three diabetic patients treated with a stable dose of sulfonylurea were randomly assigned to receive either placebo (n = 11) or pioglitazone (45 mg/day) (n = 12) for 16 weeks (89). Before and after 16 weeks of treatment, all subjects received a 75-g oral glucose tolerance test (OGTT) and peripheral insulin sensitivity was measured with a two-step euglycemic insulin clamp. After 16 weeks pioglitazone treatment significantly decreased fasting plasma glucose, mean plasma glucose during OGTT, and HbA1C without changing fasting or glucose-stimulated insulin/C-peptide concentrations. Fasting plasma free fatty acid (FFA) and mean plasma FFA during OGTT also decreased significantly after pioglitazone treatment. Pioglitazone treatment significantly decreased endogenous glucose production, whereas insulin-stimulated total and non-oxidative glucose disposal was significantly increased indicative of an improvement in hepatic and peripheral (muscle) tissue sensitivity to insulin. Subsequent work has indicated that pioglitazone at doses of 30 and 45 mg/day (but not at doses of 7.5 or 15 mg/day) improves b-cell function along with whole-body insulin sensitivity (55). The major side effects of this class of drugs are edema, weight gain, decreased hematocrit and hemoglobin, and elevated (but reversible) alanine aminotransferase activity. Unlike troglitazone, idiosyncratic hepatic reaction does not appear to be a problem with rosiglitazone or pioglitazone. The edema ranges from bothersome trace to anasarca. The mechanism of the edema production is not known. Clinically, diuretics have minimal effect on reducing the edema. While there are no published studies on this subject, it does appear that the edema is dose dependent. Weight gain may be a modest 2-4 pounds to >20 lbs (90). Due to their mechanism of action, the risk of hypoglycemia with rosiglitazone or pioglitazone monotherapy is low. Mild to moderate hypoglycemia has been reported during combination therapy with sulfonylureas or insulin (9,91). Acarbose and miglitol are members of the a-glucosidase inhibitor class of oral anti-hyperglycemic compounds that function by blocking the enzymatic degradation of complex carbohydrates in the small intestine (92,93). These compounds lower post-prandial glucose and improve glycemic control without increasing the risk for weight gain or hypoglycemia. Each drug is approved for use in the US as monotherapy, which results in a significant reduction in fasting plasma glucose by 25-30 mg/dl, post-prandial glucose by 40-50 mg/dl, and HbA1C by 0.7-1.0% (8,92,93). In addition, acarbose is approved for use in combination with insulin, metformin, or a sulfonylurea, and miglitol is approved for use in combination with a sulfonylurea. The effects of these compounds on glycemic control are additive when used in combination, presumably since their mechanism of action is different. Neither drug is approved in the US for use in combination with a meglitinide or thiazolidinedione. a?-glucosidase inhibitors are suitable approaches for patients that have mild to moderate hyperglycemia, or those patients prone to hypoglycemia or at risk for lactic acidosis. a-Glucosidase inhibitors are competitive, reversible inhibitors of pancreatic a-amylase and membrane-bound intestinal a-glucosidase hydrolase enzymes. Acarbose, the first a-glucosidase inhibitor discovered, is a nitrogen-containing pseudotetrasaccharide (Figure 1.9), while miglitol is a synthetic analog of 1-deoxynojirimycin (Figure 1.10). The mechanism of action of these inhibitors is similar but not identical. They bind competitively to the oligosaccharide binding site of the a-glucosidase enzymes, thereby preventing enzymatic hydrolysis. Acarbose binding affinity for the a-glucosidase enzymes is: glycoamylase > sucrase > maltase > dextranase (92,94). Acarbose has little affinity for isomaltase and no affinity for the a-glucosidase enzymes, such as lactase (92). Miglitol is a more potent inhibitor of sucrase and maltase that acarbose, has no effect on a-amylase, but does inhibit intestinal isomaltose (92). Clinical trials conducted to date have established that the antihyperglycemic effectiveness of acarbose and miglitol is less than 50% than that of either sulfonylureas or metformin. When used as monotherapy, acarbose primarily affects post-prandial glucose levels, which is reduced by 40-50 mg/dl after meal (8,11,92,93,95,96). In most studies, a-glucosidase inhibitors have no significant effects on either fasting insulin or whole body insulin sensitivity in patients with type 2 diabetes. However, there is some evidence that acarbose and voglibose, a structural analog of miglitol in clinical development in Japan, reduces post-prandial hyperinsulinemia in glucose intolerant individuals (97,98). Some but not all studies have reported small decreases in fasting or post-prandial triglycerides (92). Since the mechanism of action of a-glucosidase inhibitors is different from other oral agents, their effects on glycemic control are additive when used in combination. As summarized by Lebovitz (92), addition of acarbose to sulfonylurea therapy decreases HbA1C by 0.85%; addition of acarbose to metformin therapy decreases HbA1C by 0.73%; and addition of acarbose to insulin therapy decreases HbA1C by 0.54%. As for monotherapy, the predominant improvement is on post-prandial hyperglycemia. Treatment with a-glucosidase inhibitors appears to have a lower rate of secondary failures characteristic of sulfonylurea and metformin therapy. The major side effects of the a-glucosidase inhibitors are related to gastrointestinal disturbances. These occur in approximately 25-30% of diabetic patients, and include flatulence, diarrhea, bloating, and abdominal discomfort. These side effects can often be minimized by careful dose titration, and sometimes diminish with time. Acarbose is contraindicated in patients with inflammatory bowel disease, cirrhosis, or elevated plasma creatinine (>177 mmol/l). This class of drugs is associated with dose-dependent hepatotoxicity, and serum transaminase levels require monitoring for patients receiving high doses (>200 mg three times daily). Transaminase elevations, which are often asymptomatic, are reversible upon cessation of treatment. Hypoglycemia does not occur in patients on a-glucosidase inhibitor monotherapy. If hypoglycemia occurs while a patient is taking an a-glucosidase inhibitor simultaneously with a sulfonylurea, insulin or a meglitinide, the recommended action is oral administration of pure glucose, dextrose or milk. The development pipeline for new oral therapeutic agents for type 2 diabetes is encouraging and continues to expand. These intensive research and development efforts are in response to the increasing prevalence of the disease and related co-morbidities, realization by care givers that successful glycemic control will likely require combination therapy, a growing understanding of the pathophysiology of the disease, and the identification and validation of new pharmacological targets. These targets include receptors and enzymes that: enhance glucose-stimulated insulin secretion, suppress hepatic glucose production, increase skeletal muscle glucose transport and utilization, increase insulin sensitivity and intracellular insulin signaling, and reduce circulating and intracellular lipids (99,100). Due to their promise for future clinical success and because they exhibit mechanisms of action distinct from current therapies, two such emerging approaches will be highlighted here. Dipeptidyl peptidase IV (DPP-IV) Inhibition Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone secreted by L-cells of the small intestine. GLP-1 has several important biological actions including the stimulation of insulin secretion in a glucose-specific manner, inhibition of gastric emptying, suppression of glucagon secretion, and central anorexic activity (101,102). Patients with type 2 diabetes exhibit reduced levels of active GLP-1 (amino acids 7-36) along with an impaired GLP-1 response to a glucose load, and parenteral administration of GLP-1 has been shown to reduce fasting and post-prandial glycemia in patients with type 1 and type 2 diabetes (101,102). Although it possesses multiple effective clinical activities, administration of GLP-1 is not an ideal approach since it cannot be administered orally. Furthermore, endogenous (and exogenously administered) GLP-1 has undesirable pharmacokinetics; after it is secreted, it is rapidly cleaved and inactivated [plasma half-life < 1 min; (103)] by the enzyme dipeptidyl peptidase IV (DPP-IV). Thus, inhibition of DPP-IV has been suggested as a feasible alternative to circumvent the limitations of GLP-1 administration (103). This approach has recently been validated in vivo and in the clinic. A novel, orally active DPP-IV inhibitor, NVP-DPP728, has recently been identified and characterized in vitro and in vivo (104-106). In DPP-IV(+) [but not in DPP-IV(-)] transgenic rats fed either standard chow or a high-fat diet, NVP-DPP728 significantly suppressed glucose excursions after glucose challenge by inhibiting the plasma DPP-IV activity, associated with the stimulation of early insulin secretion (105). NVP-DPP728 also improved the glucose tolerance after an oral glucose challenge by potentiating the early insulin response by inhibition of plasma DPP-IV activity in aged DPP-IV(+) Wistar and F344 rats (106). In contrast, NVP-DPP728 did not affect the glucose tolerance after an oral glucose challenge in aged DPP-IV(-) F344 rats. These results indicate that treatment with NVP-DPP728 ameliorated glucose tolerance in vivo by the direct inhibition of plasma DPP-IV activity, and presumably the subsequent increase in endogenous GLP-1 action. The clinical activity of this compound as a monotherapy has recently been reported in patients at an early stage of type 2 diabetes (107). Compared with placebo, NVP-DPP728 at 100 mg (tid; n =31) significantly reduced fasting glucose by 18 mg/dl (1.0 mmol/l), prandial glucose excursions by 21.6 mg/dl (1.2 mmol/l), and mean 24-h glucose levels by 18 mg/dl (1.0 mmol/l). Similar reductions were seen in the 150-mg (bid; n = 32) treatment group. Mean 24-h insulin was significantly reduced by 26 pmol/l in both groups. In the combined active treatment groups, HbA1C was significantly reduced from 7.4 ± 0.7% to 6.9 ± 0.7%. Laboratory safety and tolerability were good in all groups. These results provide clinical proof of concept that inhibition of DPP-IV is a feasible approach for the treatment of type 2 diabetes in the early stage of the disease. The outcomes of studies involving a more diverse patient population and in combination with other oral agents are anxiously awaited. a-Lipoic acid (LA) is an eight-carbon fatty acid that is synthesized in trace quantities in organisms ranging from bacteria to man (108-110). LA functions naturally as a cofactor in several mitochondrial enzyme complexes responsible for oxidative glucose metabolism and cellular energy production (111,112). LA has been prescribed in Germany for over thirty years for the treatment of diabetes-induced neuropathy (113-115). Results from several recent controlled clinical studies indicate that this compound is safe, well tolerated, and efficacious (115). It is currently in late-stage clinical trials in the US for a similar indication. In addition to the beneficial effects of LA on diabetes-induced neuropathy, several clinical studies have reported an improvement in insulin sensitivity and whole-body glucose metabolism in patients with type 2 diabetes after continuous intravenous (iv) infusion of LA (116-119). Investigators have reported that a continuous infusion iv of LA substantially increases insulin-mediated glucose disposal (~30-50%) (116,117). Oral administration of LA (enteric-coated tablet) exerts a smaller (~20%) but nonetheless significant effect on insulin sensitivity (120,121). To overcome the abbreviated half-life of LA in plasma, a controlled release formulation of LA (CRLA) has been recently developed (122). The pharmacokinetics, safety, and tolerability of CRLA were evaluated in healthy individuals and in patients with type 2 diabetes, and this agent was found to be safe, well-tolerated, and significantly reduced plasma fructosamine in patients with type 2 diabetes (122). Also, non-controlled release LA recently has been reported to increase insulin mediated glucose disposal in patients with type 2 diabetes (123). Although the exact mechanism of action of LA is unknown, in vitro data from the laboratories of Rudich and others have indicated that LA pretreatment maintains the intracellular level of reduced glutathione (the major intracellular antioxidant) in the presence of oxidative stress, and blocks the activation of serine kinases that could potentially mediate insulin resistance (124-127). Thus, one potential explanation for the protective effects of LA might be related to its ability to preserve the intracellular redox balance (acting either directly or through other endogenous antioxidants such as glutathione), thereby blocking the activation of inhibitory stress-sensitive serine kinases including IKKbeta. This stress-sensitive kinase is a crucial regulator of the transcription factor nuclear factor-kappaB (NF-kappaB), a major target of hyperglycemia, cytokines, reactive oxygen species, and oxidative stress (128-130). The aberrant regulation of NF-kappaB is associated with a number of chronic diseases including diabetes and atherosclerosis (128,130). The ability of LA to block the activation of NF-kappaB is well established in vitro and in vivo (126,131-134). Recent evidence has linked the activation of NF-kappaB with insulin resistance (135,136). Activation of IKKbeta inhibits insulin action. Salicylates, which inhibit IKKbeta activity and block NF-kappaB activation (137), restore insulin sensitivity both in vitro and in vivo (138,139). Treatment of nine patients with type 2 diabetes for two weeks with high-dose aspirin (7 g/day) resulted in a significant reduction in hepatic glucose production and fasting hyperglycemia, and increased insulin sensitivity (140). The potential for toxicity associated with such a high dose of salicylate administered chronically precludes consideration of this agent for therapy, but the results support the rationale that IKKbeta inhibition could be a useful pharmacological approach to increase insulin sensitivity. Furthermore, LA and other agents that interfere with the persistent activation of the NF-kappaB pathway appear to be promising approaches to increase insulin sensitivity, and perhaps even as treatments for complications of diabetes in which NF-kappaB activation has been implicated (115,129). Despite the magnitude of the disease, the choice of oral agents for type 2 diabetes was limited to sulfonylureas for over 40 years. The last 10 years have witnessed the introduction of four new classes of oral antihyperglycemic therapies. Each possesses a distinct mechanism of action, which enables their use independently and, in some cases, as combination therapy. This is important since most patients with type 2 diabetes will require combination therapy to reach an acceptable level of glycemic control (8). However, despite these advances, there is still plenty of room and necessity for improvement. The successful long-term management (and hopefully prevention) of type 2 diabetes and its related co-morbidities undoubtedly requires an aggressive, comprehensive approach. This includes intervention at the pre-diabetes stage (e.g. obesity, impaired glucose tolerance) including both changes in lifestyle (i.e. dietary modification and exercise), along with pharmacological intervention that might delay or even prevent the development of the disease. However, once the disease is established and beyond the control of lifestyle modifications, treatment must be initiated and carefully monitored using existing drugs that address the current understanding of the pathophysiology: impaired insulin secretion, increased hepatic glucose production, and peripheral tissue insulin resistance. It is anticipated that emerging agents will also have a beneficial impact on these processes, but with greater efficacy and safety due to a higher degree of selectivity for their molecular targets. In addition, new information regarding the biochemistry, cell biology, and pathophysiology of the disease process is rapidly providing additional exciting opportunities for target identification, validation and subsequent drug development. The biological effects of emerging agents will not be limited to lowering blood glucose. Already, there are some new agents in clinical development that have been designed to afford a combination of benefits, including the reduction of both lipids and glucose. Other new therapies will likely address the emerging belief that there is a significant inflammatory component of the disease. Perhaps, this might be why tight glycemic control alone has experienced limited success at reducing the risk of macrovascular complications of diabetes. Targeting the risk factors for heart disease clearly requires serious attention and concomitant therapy. Based on recent clinical results, a promising treatment for one of the most common microvascular complications, neuropathy, seems on the road to gaining regulatory approval. The complexity of type 2 diabetes and associated co-morbidities will continue to present a formidable challenge for successful pharmacological treatment. However, based on the growing sophistication of 21st Century research approaches (141-144) along with the realization of the consequences of failure (1,145), there is ample support for the optimistic viewpoint that the current selection of orally active treatment options will continue to expand. |
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Go to Diabetes Index |
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Fasting
Plasma Glucose 
HDL 
