Oral antidiabetic agents: 2004

1. The importance of early aggressive treatment 

The major pathogenetic mechanisms that are responsible for the metabolic abnormalities of type 2 diabetes are insulin resistance, deficient insulin secretion, and glucose and lipid toxicity. Time course studies have shown that insulin resistance occurs early and although subtle changes in beta cell function are noted quite early, clinically significant insulin secretory inadequacy follows several years later [13]. Glucose and lipid toxicity further contribute to insulin resistance and beta cell insufficiency after derangement of intermediary metabolism has occurred.

Several clinical observations dictate that both the clinical course of type 2 diabetes and the development of microvascular complications are most favorably altered by very early and aggressive treatment of both the insulin resistance and the hyperglycemia. Several intervention studies in individuals with impaired glucose tolerance have shown that decreasing the compensatory hyperinsulinemia presumably by reducing insulin resistance or lowering postprandial plasma glucose rises can delay or prevent the development of new-onset type 2 diabetes [14], [15], [16], [17]. In the one study (TRIPOD study), the data show that reducing insulin resistance markedly decreased the rate of loss of beta cell function [16]. These data suggest that early interventions that decrease the stress of increased insulin secretion on the beta cell can delay or prevent the progressive decline of beta cell function in type 2 diabetic patients. Preservation of endogenous insulin secretory function is associated with better glycemic control. The initial treatment of type 2 diabetic patients with insulin resistance should be to decrease the insulin resistance.

Hyperglycemia is the primary cause of microvascular complications in all diabetic patients. Both the Diabetes Control and Complication Trial (DCCT) in type 1 diabetic patients and the United Kingdom Diabetes Prevention Study (UKPDS) in type 2 diabetic patients showed that intensive glycemic control compared with ordinary glycemic control significantly reduced clinically relevant retinopathy, nephropathy, and neuropathy [1], [18]. For every 1% decrease in HbA1c there was approximately a 30% decrease in microvascular complications. It is apparent in examining the time course of the development of the microvascular complications that the intensive treatment had to be in place for 3 to 4 years in the DCCT or 9 years in the UKPDS before any benefit became evident [1], [18]. These data suggested that the damage caused by early hyperglycemia takes several years before its impact lessens. The concept that the vascular bed has a memory of its previous exposure to blood glucose levels and that this memory plays a major role in the blood vessels' biology for many subsequent years has been confirmed by the Epidemiology of Diabetic Complications Study [19].

The Epidemiology of Diabetic Complications Study is a long-term follow-up of the patients who participated in the DCCT study. At the conclusion of the DCCT both the intensively treated and the ordinarily treated type 1 diabetic cohorts returned to their primary care centers for their long-term care. Most of the patients in both cohorts agreed to return to the research centers once a year to have examinations for HbA1c and retinal and kidney function. Within 2 or 3 years of care in their primary care centers the two cohorts had mean HbA1c of approximately 8%. That is, the intensively treated group could not continue to achieve mean HbA1c values of 7.1% to 7.2% outside of the intensive research setting. The ordinary control cohort was allowed to be more aggressive in their management and they improved from their previous mean HbA1cof 9%. In years 4 to 7 both cohorts had mean HbA1c of approximately 8.1%. Despite the equal HbA1c, the rate of progression of retinopathy continued to be twofold greater and nephropathy sixfold greater in follow-up years 5 and 6 in the former ordinary control cohort than the former intensively treated cohort. These data strongly support the concept that early aggressive glycemic control is essential to maximally reduce microvascular complications.

2. Strategies for treating hyperglycemia in type 2 diabetic patients 

Management of the metabolic abnormalities of patients with type 2 diabetes involves correction of hyperglycemia, blood pressure, lipid abnormalities, and the components of the metabolic syndrome. This article deals selectively with the management of hyperglycemia by oral agents, although it is obvious that such management interfaces with combination and insulin treatment and must take into account their associated effects on the other metabolic abnormalities. This being the case, the following principles must be considered when implementing any treatment program for hyperglycemia.

3. Specific oral therapies: agents to treat insulin resistance 

Two classes of oral antidiabetic agents reduce insulin resistance: biguanides (metformin) and thiazolidinediones (pioglitazone and rosiglitazone) [19]. These agents decrease insulin resistance by different mechanisms and have preferential effects on different tissues [20], [21], [22]. The thiazolidinediones act primarily on adipose tissue to decrease the metabolic consequences of obesity. It seems that increases in visceral adipose tissue result in excessive release of free fatty acids and cytokines (eg, tumor necrosis factor-α) and reduce release of the adipose tissue hormone adiponectin. The result is altered hepatic metabolism and interference in the transmission of the insulin signal within insulin-sensitive cells. These effects are responsible for the insulin resistance associated with obesity. The thiazolidinediones act on adipose tissue to decrease plasma free fatty acids, decrease tumor necrosis factor-α secretion, and improve adiponectin secretion, all of which improve insulin action in muscle, adipose tissue, and liver. Metformin increases insulin action directly in insulin-sensitive cells by a still undetermined mechanism. Metformin exerts a major effect in increasing insulin sensitivity in liver and only a minor effect in skeletal muscle [23]. Thiazolidinediones have a major effect in increasing insulin sensitivity in muscle and a somewhat lesser effect in liver [23]. Overall thiazolidinediones are about 70% more effective as a total body insulin sensitizer than metformin [24].

Improvement in insulin sensitivity in insulin-resistant type 2 diabetic patients allows endogenous insulin to be more effective and treatment of such patients with insulin sensitizers improves glycemic control. The magnitude of improvement depends on the amount of beta cell function that is present at the time therapy is started. The mean decrease in HbA1c that occurs with either metformin or thiazolidinedione monotherapy in patients with a mean baseline HbA1c of approximately 9% is 1.5% [25]. About 30% of such patients achieve a HbA1c less than or equal to 7% on maximal doses of sensitizing drugs. In the remainder of the patients, insulin secretory function is too low and either insulin secretagogues or insulin replacement needs to be added to the insulin sensitizer to achieve target glycemic goals. The addition of insulin secretagogues to insulin sensitizers can decrease HbA1c an additional 1% to 1.4% [26]. The addition of an insulin sensitizer to an insulin treatment regimen can decrease HbA1c by a mean of 0.8% to 1.2% [27] but the amount is influenced by how much the insulin dose is reduced.

There are several significant advantages to using insulin sensitizers as part of the therapeutic treatment program. As monotherapy, thiazolidinediones or metformin do not cause serious hypoglycemia because endogenous insulin secretion is still glucose dependent. Even therapy combining a thiazolidinedione and metformin is rarely associated with hypoglycemia [28]. Treatment of insulin-resistant type 2 diabetic patients with insulin sensitizers improves many of the components of the metabolic syndrome [20], [21]. The effects of metformin and thiazolidinediones on the components of the metabolic syndrome differ significantly as shown in Table 3. The effects of the two thiazolidinediones, pioglitazone and rosiglitazone, seem to be quite similar. There have been some reports suggesting that pioglitazone has a greater effect in reducing plasma triglycerides than does rosiglitazone; however, these have not been well-designed studies and there is need for a double-blind, randomized head-to-head comparator study to validate whether there is any significant difference. Metformin is the only drug used to treat hyperglycemia that has been shown to reduce macrovascular complications of type 2 diabetes [2]. Metformin treatment of overweight type 2 diabetic patients in the UKPDS reduced cardiovascular-related deaths (42%) and myocardial infarctions (39%). Sulfonylurea treatment and insulin treatment had no significant benefits on those cardiovascular events even though they lowered HbA1c the same 0.6% as metformin. Clinical trials examining the effects of thiazolidinedione treatment on the development of clinical cardiovascular events in type 2 diabetic patients are in progress.

Table 3. Comparison of the effects of thiazolidinediones and metformin on insulin resistance and the components of the Metabolic Syndrome

	Activity	Metformin	Thiazolidinediones
	Glycemic control
	FPG	↓↓	↓↓
	HbA1c	↓↓	↓↓
	FPI	↓	↓↓
	Body weight	↓	↑
	Visceral fat	↓	0
	Insulin sensitivity
	Peripheral	±	↑↑
	Liver	↑↑	↑
	Dyslipidemia
	LDL cholesterol	±	↑
	LDL particle size	0	↑
	HDL cholesterol	±	↑↑
	Triglyceride	±	↓
	Lipoprotein (a)	0	↑
	FFA	±	↓↓
	Endothelial function
	Vasodilation	↑	↑↑
	Blood pressure	0	↓
	Adhesion molecules		↓
	Muscle proliferation		↓
	Procoagulant state
	PAI-1	↓	↓
	Fibrinogen
	Inflammation
	C-reactive protein	↓	↓↓
	Mesangial function
	Microalbuminuria	0	↓

Abbreviations: FFA, free fatty acid; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAI, plasminogen activator inhibitor. 0, no effect; ↓, decrease; ↓↓, marked decrease; ↑, increase; ↑↑, marked increase. Data from Lebovitz HE, Banerji MA. Treatment of insulin resistance in diabetes mellitus. Eur J Pharmacol 2004;490:135–46.

There are additional major differences between the effects of thiazolidinediones and metformin. Metformin treatment is usually associated with some weight loss. Most clinical studies show a mean weight loss with metformin treatment of approximately 1 to 2 kg [29]. Thiazolidinedione treatment is usually associated with a mean weight gain of 1.5 kg at intermediate doses and 3.5 kg at high doses [30]. The side effects of metformin include abdominal discomfort and diarrhea, which occur in 10% to 20% of patients on maximal doses, and a very rare occurrence of lactic acidosis [29]. The gastrointestinal symptoms can be minimized by initiating metformin therapy with 500 mg with the evening meal, increasing the dose to 500 mg twice a day, and slowly titrating the dose to 1000 mg twice a day with meals. The longer-acting preparations, such as Glucophage XR, cause less gastrointestinal side effects. The few cases of metformin-induced lactic acidosis that have been reported occurred in individuals with decreased renal function, symptomatic heart failure on therapy, or an underlying metabolic acidosis [31]. The major side effects of thiazolidinedione treatment are an increase in adipose tissue and fluid retention. The increase in adipose tissue is selective for the subcutaneous region [32]. The visceral adipose tissue either is unchanged or decreases slightly. The fluid retention manifests itself as mild to moderate peripheral edema, which occurs in 4% of patients on monotherapy [33]. When thiazolidinediones are combined with insulin, edema is seen in approximately 15% of the patients [33]. A rare type 2 diabetic patient on thiazolidinediones develops heart failure. Such patients are usually older, are on maximal doses of the thiazolidinedione, are also taking insulin, and have a prior history of cardiovascular disease or renal failure [33]. The mechanism seems to be the increase in plasma volume in type 2 diabetic patients who had asymptomatic compensated heart failure. Treatment of the fluid retention with loop diuretics is of limited benefit. Angiotensin-converting enzyme inhibitors and aldosterone antagonists have been used with limited success to treat the fluid retention [33]. According to a recent consensus panel convened by the American Diabetes and American Heart Associations patients who are at risk for developing congestive heart failure and could benefit from thiazolidinedione treatment should be started on very low doses, titrated up slowly, and have careful monitoring of body weight and edema [33]. If excess weight gain or edema is noted despite attempts to treat it, the thiazolidinedione should be discontinued.

Metformin is administered twice a day and the maximal benefits on glycemic control are seen at 2000 mg/d. Pioglitazone is administered once daily in doses of 15, 30, or 45 mg/d. Rosiglitazone is administered either once or twice a day in doses ranging from 2, 4, or 8 mg/d.

4. Specific oral therapies: agents to increase insulin secretion 

In insulin-resistant type 2 diabetes, hyperglycemia occurs when insulin secretion is inadequate to overcome the degree of insulin resistance that is present. The natural history of the development of type 2 diabetes is a progressive decline in beta cell function. This was clearly documented in the UKPDS, which also showed that this decline in beta cell function was not altered by treatment with diet, metformin, sulfonylureas, or insulin [10].

The decline in beta cell function is caused by a decreased ability of glucose to cause closure of an ATP-dependent potassium channel in the plasma membrane of beta cell [34], [35]. The normal mechanism for glucose stimulation of insulin secretion involves the following steps [34], [35]. Glucose from the plasma compartment is rapidly transported into the beta cell, phosphorylated, and metabolized to generate ATP. Special enzymes in the beta cell (Glut-2 glucose transporter and glucokinase) allow this process to occur quantitatively so that the intracellular ATP:ADP ratio accurately reflects the plasma glucose concentration. The plasma membrane of the beta cell contains a potassium channel whose function is regulated by the ATP:ADP ratio and a voltage-dependent calcium channel. When the plasma glucose is low the potassium channel is open and extruding potassium from the beta cell. The plasma membrane is appropriately polarized and the calcium channel is closed. As the plasma glucose rises, the ATP:ADP ratio increases, which causes the ATP-dependent potassium channels to close. Closure of the ATP-dependent potassium channel causes depolarization of the adjacent plasma membrane, which results in opening of the voltage-dependent calcium channels in that portion of the depolarized membrane. The open calcium channels allow calcium to be transported from the extracellular compartment into the cytoplasm of the beta cell. Increases in cytosolic calcium ion concentrations linearly increase the release of insulin from the beta cell granule into the plasma compartment. The impaired release of insulin, which is characteristic of the early stages of type 2 diabetes, is a delayed and impaired ability of plasma glucose fluctuations appropriately to regulate closure of the ATP-dependent potassium channel.

As the duration of type 2 diabetes increases, the functional defect in beta cells is compounded by an increase in apoptosis and a decrease in beta cell mass. The mechanism responsible for the decrease in mass is unclear but the consequence is that type 2 diabetic patients become more insulin deficient with time.

In the first 4 or 5 years after the onset of clinical type 2 diabetes the functional defect in insulin secretion can be ameliorated by pharmacologic agents, which act directly on the ATP-dependent potassium channel and augment its closure by glucose. These agents are the insulin secretagogues, of which there are three distinct classes in clinical use: (1) sulfonylureas, (2) meglitinides, and (3) phenylalanine derivatives. All of these agents interact with the regulatory subunit of the ATP-dependent potassium channel and directly stimulate its closure [34], [36]. There are subtle differences in the specific binding site and characteristics of binding among the three classes of insulin secretagogues, which modulate differences in their pattern of insulin release [35], [37].

The commonly prescribed sulfonylureas include glyburide, glipizide, and glimepiride. The glyburide is formulated as regular and micronized. The glipizide is formulated as short acting and slow release. Table 4 lists these formulations and their characteristics. The meglitinide that is available is repaglinide and the phenylalanine derivative that is marketed is nateglinide. Their characteristics are also listed in Table 4.

Table 4. Properties of commonly prescribed insulin secretagogues

	Generic name	Daily dose	Duration of action	Comments
	Glyburide	2.5–20 mg	>24 h	Absorption is incomplete and variable
				Hypoglycemia is the most common and severe
				Blocks ischemic preconditioning
	Glyburide micronized	1–8 mg	>24 h	More consistent absorption
	Glipizide	2.5–20 mg	>12 h	Relatively short acting
				Hypoglycemia less severe and about half as frequent as glyburide
	Glipizide-GITS	5–20 mg	24 h	Hypoglycemia and weight gain reported to be quite low
	Glimepiride (Amaryl)	1–8 mg	24 h	Hypoglycemia frequency and severity < half that of glyburide
				No interference with ischemic preconditioning
	Repaglinide (Prandin)	1–4 mg with each meal	5–6 h	Low incidence of hypoglycemia
				Weight gain less than with sulfonylureas
	Nateglinide (Starlix)	60–120 mg with each meal	3–4 h	Very low incidence of hypoglycemia
				Little data on weight gain

The clinically relevant insulin secretory defects in type 2 diabetes are (1) a 30- to 60-minute delay in meal-mediated insulin secretion, (2) a deficient quantity of insulin secretion, and (3) a progressive loss in beta cell function with time [34], [36], [38]. Administration of sulfonylureas does not significantly alter the delay in meal-mediated insulin secretion.

Sulfonylurea treatment augments fasting insulin secretion and the second or late phase (after 60 minutes) of meal-mediated insulin secretion [34], [36]. The consequence of these pharmacologic actions is a lowering of the fasting plasma glucose but very little decrease in the postprandial plasma glucose excursion. Sulfonylureas do not stimulate insulin biosynthesis. The two new insulin secretagogues, repaglinide [39], [40] and nateglinide [41], [42], were specifically designed to increase early meal-mediated insulin secretion. They are able to do so because they are rapidly absorbed and have rapid binding kinetics to the regulatory subunit of the ATP-dependent potassium channel [35], [37], [39], [40], [41], [42]. They can be taken at the time of the meal and are able to facilitate early meal-mediated insulin secretion. This provides for a lower early and a shorter duration of postprandial glucose rise. These insulin secretagogues in contrast to sulfonylureas decrease the postprandial plasma glucose excursions [39], [40], [41], [42], [43].

Sulfonylurea drugs have a long duration of action because of their pharmacokinetic properties and their binding kinetics to the regulatory subunit of the ATP-dependent potassium channel [34], [36]. Repaglinide has a prolonged low-affinity binding to the regulatory subunit of the ATP-dependent potassium channel, and although it has a rapid onset of insulin release it also continues stimulating some insulin secretion for several hours, which explains its additional effect in lowering fasting plasma glucose [37], [44]. In contrast, nateglinide has a rapid onset and short duration of insulin secretory action because it rapidly dissociates from the regulatory subunit of the ATP-dependent potassium channel [37], [41]. Its beneficial effects are primarily in lowering postprandial plasma glucose excursions [41].

Understanding the pharmacology of the various insulin secretagogues explains the differences in their clinical effects (Table 5) [34], [36]. Sulfonylureas have a prolonged duration of action. Their primary beneficial effects are to decrease fasting and between-meal hyperglycemia. They have minimal effects on postprandial glucose excursions. Because of their prolonged actions they can lead to severe fasting and late postprandial hypoglycemia [34], [45], [46]. This is particularly so when meals are delayed or missed [47]. Severe sulfonylurea-induced hypoglycemia is a rare complication that is more likely to occur in older individuals and in those with underlying cardiovascular or kidney disease [36], [45], [46]. When it occurs, patients need treatment for several days in an emergency ward or intensive care unit. Glyburide treatment has been reported to have a significantly greater frequency of severe hypoglycemia than other sulfonylureas [34], [45], [46].

Table 5. Comparison of classes of insulin secretagogues

		Sulfonylureas	Repaglinide	Nateglinide
	Dosing	Once or twice daily	With each meal	With each meal
	FPG	↓ 50 to 60 mg/dL	↓ 50 to 60 mg/dL	↓ 20 mg/dL
	PPG excursion	Slight effect	Moderate effect	Major effect
	PP insulin secretion	↑ late phase	↑ early and late phases	10 min to 4 h
	Hypoglycemia	Fasting and late PP	Less than sulfonylureas	Uncommon
	Weight gain	1 to 3 kg	Less than sulfonylureas	?
	HbA1c	↓ 1.5%	↓ 1.5%	↓ 0.8%
	Cost	Inexpensive	Expensive	Expensive

Abbreviations: FPG, fasting plasma glucose; PP, postprandial; PPG, postprandial plasma glucose excursion.

Nateglinide has only minor effects on fasting and between-meal hyperglycemia but is very effective in reducing postprandial glucose excursions [41], [48]. Because of its rapid onset and short duration of action it must be taken with each meal. A major advantage is that missed meals and delayed meals are unlikely to cause significant hypoglycemia. Indeed, reported rates of hypoglycemia are quite low. Because of its minimal effects on fasting hyperglycemia nateglinide is usually given in combination with other antihyperglycemic agents [42].

Repaglinide has properties that combine the benefits of both sulfonylureas and nateglinide. It primarily facilitates early meal-mediated insulin secretion but it also has some modest prolonged insulin secretory function [43], [44], [47]. As a result, it lowers fasting plasma glucose and also decreases postprandial glucose excursions [40], [44]. It is taken with each meal. If meals are delayed or missed there is a minimal likelihood of having significant hypoglycemia [47]. Clinical trials comparing treatment with repaglinide versus a sulfonylurea show similar degrees of glycemic control with repaglinide causing somewhat less hypoglycemia and weight gain [44].

The beneficial effects of sulfonylureas on glycemic control occur during the first several years following diagnosis. The effects decrease with duration of diabetes. In the UKPDS trial the percentage of type 2 diabetic patients that achieved HbA1c less than 7% on sulfonylurea monotherapy decreased from 50% after 3 years to 34% after 6 years to 24% after 9 years [49]. Many type 2 diabetic patients need insulin replacement therapy rather than insulin secretagogue therapy after 5 to 10 years of clinical disease [50], [51].

5. Specific oral therapies: agents to delay carbohydrate digestion and absorption 

Postprandial plasma glucose levels are determined by the nutrients being ingested, the gastrointestinal hormones being secreted in response to the nutrients, pancreatic insulin and glucagon secretion, and the responsiveness of the liver and peripheral tissues to the secreted insulin and glucagons. Changing the digestion of complex carbohydrates decreases the rate of monosaccharide absorption and lowers postprandial plasma glucose and, secondarily, plasma insulin levels [52].

Complex carbohydrates are digested to oligosaccharides in the small intestine by pancreatic lipase. The oligosaccharides are then cleaved to monosaccharides by a group of enzymes (α-glucosidases) located in the brush border of the enterocytes and the monosaccharides are absorbed [52]. Normally, most of the digestion and absorption of carbohydrates occurs in the duodenum and upper jejunum.

Competitive inhibitors of the α-glucosidase enzymes have been made and when given to diabetic patients decrease the postprandial plasma glucose rise [52], [53], [54]. These drugs decrease the rate of digestion of oligosaccharides in the duodenum and upper jejunum. The oligosaccharides proceed through the small intestine where they are slowly cleaved and absorbed. This results in a decrease in the mean peak postprandial glucose of approximately 50 mg/dL [52], [53], [54]. The mean fasting plasma glucose during chronic therapy with α-glucosidase inhibitors is reduced approximately 20 mg/dL and the mean HbA1c by 0.5% [52], [53], [54].

The major α-glucosidase inhibitor used is acarbose, which is a nonabsorbable agent. The recommended dose is 50 mg taken with the start of each meal. The distal jejunum and ileum normally have very low concentrations of α-glucosidase enzymes, which means that during the initiation of treatment much of the undigested oligosaccharide passes into the colon where it is metabolized by the bacteria to short-chain fatty acids, hydrogen, methane, and carbon dioxide. That causes the side effects of abdominal pain, diarrhea, and flatulence. The side effects can be minimized by initiating therapy with 25 mg with the evening meal. After a week or so the dose can be increased to 25 mg with breakfast and the evening meal. If minimal or no symptoms occur the dose titration can be slowly increased to 50 mg with each meal. Occasional patients may require 100 mg with each meal. Dose increases are determined by the 1-hour postprandial plasma glucose levels, which ideally should be less than or equal to 180 mg/dL.

Acarbose and miglitol are the α-glucosidase inhibitors on the market. The usual dose is 50 mg with each meal. The α-glucosidase inhibitors can be combined with all other classes of antihyperglycemic therapy.

6. Combination therapies 

Combination therapy should be the treatment of choice in most patients with type 2 diabetes. Acceptance of the importance of combination therapy has spawned the production of several fixed combinations, such as glyburide and metformin (Glucovance), metformin and glipizide (Metaglip), metformin and rosiglitazone (Avandemet), and glimepiride and rosiglitazone (Avandaril). These fixed combinations provide for better compliance and lower cost because they require one copay.

The use of metformin and a thiazolidinedione provides maximum effects on insulin resistance with diminished side effects. This combination is quite useful in patients in the early stages of hyperglycemia when insulin resistance is the predominant defect and insulin secretion is still well maintained. In the more advanced stages of hyperglycemia when insulin secretory deficiency is more marked, a combination of an insulin secretagogue and one or more insulin sensitizers is more appropriate. α-Glucosidase inhibitors or nateglinide can be added specifically to improve recalcitrant postprandial hyperglycemia. The choice between adding a third oral agent or adding basal insulin therapy should be dictated by the cost and the magnitude of the HbA1c at the time the therapy change is being considered.

7. Summary 

The appropriate management of patients with type 2 diabetes presents many challenges to health care providers. The disease is increasing at alarming rates because of the population's changing lifestyle. The first several years of type 2 diabetes are likely to be unrecognized and untreated. The pathophysiology of type 2 diabetes dictates that treatment of insulin resistance should be an early and central focus for every therapeutic program. Effective treatment of insulin resistance can slow the rate of beta cell deterioration and improve the cardiovascular risk factors, which are part of the metabolic syndrome. When beta cell function deteriorates it is necessary to improve insulin availability either by adding an insulin secretagogue or providing insulin replacement. Treatment must focus on control of both fasting and postprandial plasma glucose levels if glycemic targets are to be met and chronic complications are to be avoided. Appropriate control of blood pressure, lipids, and the predilection to thrombotic disease are equally important targets. The pharmacologic tools currently available are capable of allowing most patients with type 2 diabetes to achieve good metabolic control. Implementation of early combination therapy is essential if glycemic targets are to be met.