The pharmacological management of type 2 diabetes is rapidly evolving. We have moved from a situation in which we had meagre options for therapy to a plethora of available drugs -- making therapeutic choices will increasingly pose management challenges for treating physicians.

In the U.S., until about four years ago, sulphonylureas were the only type of oral anti-diabetic agent available on the market. Once patients failed this therapy, the only pharmacological alternative was insulin treatment. Today, there are multiple options for initial monotherapy, as well as combination therapy, that are successful in improving blood glucose control. Besides the obvious advantage to combination therapy, in terms of possible additive or synergistic effects to reduce blood glucose levels, there is an additional important concept that emerges from the availability of multiple drugs: the concept of mechanism-specific treatments.

Mechanism-specific Therapies

Although the underlying etiologies of type 2 diabetes are not understood at this time, some essential pathogenetic mechanisms have been well described. We now know that the pathophysiology of type 2 diabetes includes resistance to insulin action as well as dysfunction in insulin secretion. Patients with type 2 diabetes are also known to have excess hepatic glucose production that contributes to elevated blood glucose concentrations.

We are entering an era where therapy may be designed to target one or more of these pathogenetic mechanisms, rather than using a list of antidiabetic agents in empirical fashion. As more new antidiabetic agents are discovered, which can be anticipated in future years, this will become an increasingly important approach to diabetes management. Although there is some overlap in terms of the target tissues for biological action among some current drugs, we will take a mechanistic approach in this Cyberounds^® -- we will classify and discuss the different agents according to their mode of action.

Type 2 Diabetes Is Not Only a Disease of Carbohydrate Metabolism 

Patients with type 2 diabetes have multiple associated disorders, in particular, hypertension, obesity, hyperlipidemia and accelerated atherosclerosis. Hypertension and dyslipidemia are commonly found in patients with diabetes and can contribute to the development of long-term complications. In turn, diabetes may influence the progress of these disorders as well. Thus, the treatment of the associated disorders is now an integral part of diabetes management. Treatment goals for hypertension and dyslipidemia are provided in all ADA (American Diabetes Association) recommendations for management. When these disorders are also present, their quantitative management also needs to be considered when choosing antidiabetic medications. A few examples will be given below where choice of antidiabetic agent might be determined, at least in part, by the presence of associated disease. This applies, particularly, to management of associated dyslipidemia - a number of anti-hyperglycemic agents also have beneficial effects on lipid disorders and may, therefore, be a better choice of medication to address both issues simultaneously.

Not By Drugs Alone

It is important to stress that drug therapy should never be used without concomitant and/or preceding non-pharmacological therapies. These include diet, physical activity and education. Asymptomatic, newly diagnosed diabetic patients should have a trial of diet and exercise before being placed on pharmacotherapy. Even when drug treatment has begun, optimal therapy should include life-style changes and education as part of management. Nevertheless, in this Cyberounds^®, we will focus, exclusively, on medications, with an emphasis on the newer oral agents.

Goals of Therapy

Tight control reduces the long-term microvascular and macrovascular complications of type 2 diabetes. Much of the evidence for this originated from extrapolation out of the Diabetes Control and Complications Trial (DCCT) study in type 1 diabetes but, now, with the results of the U.K. Prospective Diabetes Study (UKPDS), there is direct evidence for a beneficial effect in type 2 diabetes as well.

Using the data from these large multicenter studies, the ADA has set guidelines for therapeutic goals. These include a target level of 7% for HbA1c, or one percent above the upper limit of normal in other glycated hemoglobin assays. Fasting plasma glucose (FPG) should be 100 - 120 mg/dl (5.5-6.6 mmol/l) and postprandial glucose 100-180 mg/dl (5.5-10 mmol/l). When starting oral agents, patients should be rapidly titrated to their optimal dose -- with provider visits at 2-4 week intervals. Frequent evaluation of patients soon after initiation of treatment is recommended so that the efficacy of monotherapy can be evaluated within weeks rather than months. In the event of failure of primary therapy, a decision can be made about the need for combined therapy without unnecessary delay.

Table 1. Classes of Agents Available for Treatment of Type 2 Diabetes.

Mechanism of Action	Class of Agent	Indication for Use
Stimulates insulin secretion	Sulphonylureas Benzoic Acid Derivative	Primary or secondary Rx
Suppresses HGP*	Biguanides	Primary or secondary Rx
Insulin sensitizer	Thiazolidinediones	Secondary Rx
Reduces postprandial plasma glucose excursion	Alpha-glucosidase Inhibitors	Secondary treatment
Insulin replacement	Insulin/insulin analogues	Failure of oral agents

*HGP, hepatic glucose production

Insulin Secretagogues

Sulphonylureas

Mechanism of Action

This class of agents was the mainstay of the treatment of type 2 diabetes for many years. Their mechanism of action is primarily to stimulate insulin secretion by a direct effect upon the beta cells. They interact with specific receptors on the plasma membrane that initiate a series of events: closure of ATP-sensitive potassium channels, depolarization of the beta cell membrane, an influx of calcium and a signal to increase insulin secretion. This increase in insulin secretion accounts for most of the beneficial effects of the sulphonylurea class of oral agent that include suppression of hepatic glucose production and enhancement of glucose disposal into fat and muscle tissue.

Clinical Effects

Sulphonylureas can be used as primary monotherapy and still remain the most popular group of medications used for this purpose. In part, this may be a function of physicians' habits but an important factor is their low cost. Most of the second generation sulphonylureas are now generic and the first generation agents are the cheapest oral agents available. SU are effective hypoglycemic agents. Reductions of HbA1c of 1.5-2.0% are common in most patients when treatment is initiated. However, the UKPDS and other studies have demonstrated that SU failure can be expected in 44% of patients within six years of beginning treatment. Failure occurs more rapidly in younger, more hyperglycemic individuals and those with lower insulin secretion at the start of treatment. On average, secondary failure occurs at a rate of 7-8 % per year after initial successful improvement of glucose control. While this may sound like a high rate of failure for sulphonylureas, it is important to realize that similar large-scale data do not exist yet for other agents described below. Thus, the failure rate data should not be interpreted to mean that sulphonylureas, as a group, are not good agents to use.

Side Effects

Hypoglycemia and weight gain are the two most frequent side effects. Since the UGDP (University Group Diabetes Program) study, published in the 1970s, the possibility of a deleterious influence on coronary artery disease has been raised periodically. However, the results of the UKPDS indicate that sulphonylureas are no more likely to increase coronary artery disease than any of the other agents tested (insulin and metformin). There is little or no effect of sulphonylureas on plasma lipids.

Benzoic Acid Derivative (Repaglinide)

Mechanism of Action

Repaglinide is a benzoic acid derivative that also stimulates insulin secretion by interacting with the ATP-sensitive K+ channel but via an apparently different receptor than the sulphonylureas. It is, therefore, regarded as a non-sulphonylurea insulin secretagogue.

Clinical Effects

Repaglinide is an effective agent to stimulate insulin secretion. It is rapidly absorbed and has a short half-life, requiring multiple daily doses given with each meal. Repaglinide's pharmacokinetics have obvious disadvantages to the patient in terms of convenience but also have potential benefits discussed below. Repaglinide seems to have little effect on lipids.

Side Effects

Like the sulphonylureas, this insulin secretagogue is associated with weight gain and hypoglycemia. However, based on its short duration of action, one might expect that hypoglycemia might be less of a problem with repaglinide - and this appears to be the case. Early evidence suggests that repaglinide might also be useful in type 2 diabetic patients with erratic lifestyles who occasionally miss meals -- skipping a meal appears to be associated with a smaller decrement of blood glucose than the longer acting, second generation sulphonylurea class of drugs, particularly if repaglinide is simultaneously skipped.

* This is not a complete list of 1st generation sulphonylureas. Their only current indication is cost. When costs of generic second generation sulphonylureas become low enough, there will not be an indication for first generation agents any longer in the treatment of diabetes.

Reduction of Hepatic Glucose Production

Metformin

Mechanism of Action

Metformin is not a new medication, though it was only approved by the FDA for use in the United States in 1995. Extensive experience in Europe and elsewhere in the world was available by the time it was introduced in the U.S.. Its primary effect is to enhance insulin-mediated inhibition of hepatic glucose production and stimulation of glucose transport into muscle. The mechanism of action of metformin is not understood.

Clinical Effects

Metformin can also be used as primary monotherapy. It is useful in patients who are also obese because it is not associated with the weight gain seen with sulphonylureas and may even be associated with mild weight loss. Metformin is also as capable as sulphonylureas in reducing HbA1c and is, therefore, an effective choice for monotherapy. HbA1c is also reduced by about 1.5%. An additional benefit of metformin is its effect upon lipid metabolism. It reduces triglyceride and LDL cholesterol levels by about 10% and also has an effect to lower serum free fatty acids.

Side Effects

Side effects are more common with metformin. Up to 30% of patients develop gastrointestinal side effects, though these may be mild and transient, especially if dose titration is done slowly. The largest concern with the use of metformin is the potential for lactic acidosis. However, this is a very rare side effect of the drug, particularly if care is taken not to prescribe metformin when it is contraindicated. Contraindications to its use are: evidence of renal insufficiency (elevated serum creatinine >1.4 [women], >1.5 [men] mg/dl), significant liver disease, chronic alcoholism; or disorders associated with poor perfusion and, thus, a propensity for lactic acidosis, such as congestive heart failure. Importantly, side effects that do not occur during the use of metformin as monotherapy are hypoglycemia and, as mentioned above, weight gain.

Insulin Sensitizers

Thiazolidinediones

Mechanism of Action

The thiazolidinediones (TZD) enhance insulin action in insulin-dependent tissues, particularly muscle and fat, and, thus, are known as insulin sensitizers. Their action requires the presence of insulin, so TZDs are not indicated in type 1 diabetes or insulinopenic type 2 diabetes. The TZDs bind to nuclear receptors known as PPAR g (peroxisome proliferator activated receptor), which are thought to mediate the action of this class of agents.

Clinical Effects

TZDs, when used as monotherapy, are effective in reducing HbA1c. Average drop in HbA1c levels is about 1%. They are also effective in combination therapy with either sulphonylureas or metformin. Of all the oral agents, TZDs have the slowest response time to initiation of treatment or change of dosage. Increase in dose should not be prescribed until 4-6 weeks have elapsed at a given dose level because it takes that long for maximal biological effect to occur. This slow onset of action is probably because unlike other antidiabetic agents, TZD's require gene activation and transcription to occur before biological effects are observed. About 25% of patients do not respond to initial therapy. We believe non-response results from insufficient insulin secretion which appears necessary (in addition to insulin sensitizing) for improving glucose control. Non-responders can be identified by measuring fasting C-peptide concentrations (<1.5 ng/dl or 0.5pmol/ml). Some TZDs also have beneficial effects upon the plasma lipid profile. Troglitazone was designed with a lipid lowering effect in mind when a side chain for the bioactive TZD molecule was developed. Troglitazone lowers triglyceride concentrations and increases HDL. Pioglitazone also decreases triglycerides.

Side Effects

The major side effect, seen with troglitazone, the first TZD to be approved by the FDA, is hepatotoxicity. The effects observed range from an elevation in liver enzymes, which is reversible, to hepatic failure that has led to some deaths in a small number of patients. Although not observed initially in premarketing trials, the more severe hepatotoxicity was noted once large numbers of patients were placed on this drug after approval for marketing. The FDA has now reversed approval of troglitazone for primary monotherapy and requires monthly monitoring of liver enzymes during the first year of treatment. Two more versions of the TZD class that have recently been approved by the FDA, rosiglitazone and pioglitazone, do not appear to be associated with hepatotoxicity. However, the FDA requires monitoring of serum enzyme levels at this time, albeit not as frequently as with troglitazone (quarterly within the first year).

Other side effects of TZD are mild elevations of LDL cholesterol and fluid retention. The latter side effect is the reason that care should be taken in prescribing TZDs to patients with congestive heart failure; for it has not been tested in patients with advanced degrees of heart failure. An advantage of TZD is that hypoglycemia does not occur when it is used as monotherapy because decreasing blood glucose levels, in response to treatment, are associated with a reduction in insulin concentrations as well.

Reduction of Postprandial Glucose Concentrations

Glucosidase Inhibitors

Mechanism of Action

These medications act in the intestine to inhibit the action of alpha-glucosidase enzymes which are responsible for breaking down complex carbohydrates into monosaccharides. This results in delay of absorption of carbohydrates and, as a consequence, a slower increase in blood glucose levels after a meal.

Clinical Effects

The primary effect of these agents is to reduce the postprandial excursion of blood glucose. The glucosidase inhibitors produce an overall improvement in glucose control with reduction of HbA1c that is less than 1%. They are not, therefore, usually used for primary monotherapy unless a patient with mild fasting hyperglycemia appears to have large postprandial increases in blood glucose. These agents are most useful in combined therapy, especially where postprandial glucose is unsatisfactorily controlled with one agent alone. As reported in some studies, the inhibitors produced a mild reduction in triglycerides but this may be a consequence of improved diabetes control.

Side Effects

Gastrointestinal side effects are common, affecting up to 30% of patients. Bloating, flatulence, diarrhea and abdominal discomfort and pain are the major complaints but can be reduced by eating less carbohydrate. Hypoglycemia is not a side effect of monotherapy with alpha-glucosidase inhibitors. However, it is important to inform patients that if they develop low blood glucose levels, treatment must be with glucose. Complex carbohydrates will be unable to rapidly correct blood glucose concentrations because of the mechanism of action of the medication. Weight gain does not occur with these agents.

Insulin Replacement

Eventually, many patients with type 2 diabetes will go on to receive insulin treatment. It is clear that the natural history of this disorder is progressive and that insulin secretion fails with time, leading to failure of all of the oral agents that have been around long enough to be studied for prolonged periods. The UKPDS (UK Prospective Diabetes Study) has delineated this for all but the most recent medications that were not available for testing during that comprehensive study. It therefore follows that, if the beta cell mass is failing to maintain glucose control with the help of the oral agents discussed above, insulin replacement must, eventually, be an option. The use of insulin will not be addressed in this Cyberounds^®.

Combination Therapy

As mentioned above, primary therapy can begin with a sulphonylurea or metformin. The use of a thiazolidinedione, as primary therapy, will need to be evaluated with the newer agents now available. The goal of therapy is to achieve ADA guidelines for glucose control, i.e., a HbA1c of <7%. If treatment with one oral agent fails to achieve this goal, the following steps are recommended:

1. Evaluate the non-medication regimen. This can be usefully done each time a medication(s) fails to achieve goals before adding or switching to another agent. Reevaluate the role of diet, exercise and education. It is particularly important that the physician or trained nurse or diabetes educator ensure that the patient understands the use of the medication that has failed -- this, ideally, requires that the drug is brought into the office for visual confirmation and that standard questioning occurs about dosage and timing.
2. Add another medication.
   1. Add an insulin secretagogue if this has not been used as primary therapy. This can be added to metformin.
   2. If an insulin secretagogue was used as a primary therapy, add an inhibitor of HGP (metformin) or an insulin sensitizer (thiazolidinedione). The presence of dyslipidemia may influence the choice.
   3. If postprandial glucose is elevated (>180mg/dl or 10mmol/l), despite achieving relatively good preprandial levels, an alpha-glucosidase may be added to assist in achieving HbA1c goals. Thus, blood glucose measurements (SMBG) will also influence your choice of combination therapy. In addition to measurement of HbA1c, SMBG should be followed to evaluate postprandial glucose excursions.

If treatment with two oral agents fail, the following approach is recommended next:

1. Evaluate the non-medication regimen. This is another opportunity to repeat the process described above. It should be individually tailored to each patient so that unnecessary effort is not wasted in repeating this step. A diabetes educator should determine the need and extent of this evaluation but it should not be ignored.
2. Add another medication. The major decision here is whether to start insulin at this point or, instead, try another oral agent (a third). This decision should be guided by some of the following considerations:
1. How poor is the glucose control? If HbA1c is greater than 3.0% above the normal range for the assay, the likelihood of achieving the ADA goals with a third oral agent is small and insulin should be started.
2. Should the target HbA1c be 7%? A less stringent target may be appropriate in a minority of patients so that two or three medications may suffice. Age of the patient and presence of long-term complications of diabetes may influence this decision.
3. Patient's wishes regarding choice of therapy (insulin versus a second or third oral agent).
4. Other concomitant diseases (e.g., renal disease will affect the use of metformin, liver disease the use of thiazolidinediones).
5. Other concomitant treatments (patients taking many pills should be treated with as few medications as possible - perhaps insulin alone will be the best choice rather than two or certainly three sets of pills).
6. Cost. This will play an important role since there is a wide range of costs for the medications reviewed here. In general, the most recent additions to the armamentarium are the most costly and insulin, depending on dosage, is also cheaper than the newest oral agents.

Future Antidiabetic Medications

Many pharmaceutical companies are working to produce newer agents that will assist in the management of type 2 diabetes. These include novel classes of drugs as well as new insulin sensitizers and stimulators of insulin secretion. An example of the last class of agents is the D-phenylalanine derivative, nateglinide (Starlix^®), which is a rapid-onset, short-duration insulinotropic agent - similar to repaglinide in effect, though, chemically, quite different. This drug is an effective stimulator of acute insulin secretion and is used prior to meals.(5) It may be useful as primary therapy once it appears on the market.