Introduction

The pharmacological management of type 2 diabetes is rapidly evolving with many options now available for initial monotherapy, as well as combination therapy that successfully improves blood glucose control.

Although the underlying etiologies of type 2 diabetes are not understood at this time, some essential pathogenetic mechanisms have been well described -- resistance to insulin action as well as dysfunction in insulin secretion and excess hepatic glucose production that contributes to elevated blood glucose concentrations. Although there is some overlap in terms of the target tissues among some current drugs, we will classify and discuss the different agents according to their mode of action.

Patients with type 2 diabetes have multiple associated disorders, in particular, hypertension, obesity, hyperlipidemia and accelerated atherosclerosis. 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.

Drug therapy should never be used without concomitant and/or preceding non-pharmacological therapies -- 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.

Tight control reduces the long-term microvascular and macrovascular complications of type 2 diabetes. ADA guidelines for therapeutic goals 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). 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.

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

Insulin Secretagogues

n Sulphonylureas were the mainstay of the treatment of type 2 diabetes for many years. They stimulate insulin secretion by a direct effect upon the beta cells resulting in suppression of hepatic glucose production and enhancement of glucose disposal into fat and muscle tissue. They can be used as primary monotherapy and still remain the most popular group of medications largely because of their low cost. Reductions of HbA1c of 1.5-2.0% are common in most patients when treatment is initiated. However, SU failure can be expected in 44% of patients within six years of beginning treatment, occurring more rapidly in younger, more hyperglycemic individuals and those with lower insulin secretion at the start of treatment. Similar large-scale data do not exist yet for other agents and, thus, the failure rate data should not be interpreted to mean that sulphonylureas, as a group, are not good agents to use. Hypoglycemia and weight gain are the two most frequent side effects. They have little or no effect on plasma lipids.

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. Rapidly absorbed. with a short half-life, multiple daily doses, given with each meal, are required. Repaglinide seems to have little effect on lipids. Like the sulphonylureas, it is associated with weight gain and hypoglycemia. Based on its short duration of action, hypoglycemia is less of a problem with repaglinide and it may, therefore, be useful in type 2 diabetic patients with erratic lifestyles who occasionally miss meals, particularly if repaglinide is simultaneously skipped.

Reduction of Hepatic Glucose Production

Metformin enhances insulin-mediated inhibition of hepatic glucose production and stimulation of glucose transport into muscle. The mechanism of action of metformin is not understood. It can be used as primary monotherapy and is useful in obese patients because it is not associated with the weight gain seen with sulphonylureas and may even be associated with mild weight loss. It reduces triglyceride and LDL cholesterol levels by about 10% and also has an effect to lower serum free fatty acids. Side effects are more common -- up to 30% of patients develop mild gastrointestinal side effects. Lactic acidosis is a serious, but rare, side effect. Importantly, metformin is not associated with hypoglycemia.

Insulin Sensitizers

Thiazolidinediones (TZD) enhance insulin action in insulin-dependent tissues, particularly muscle and fat. Their action requires the presence of insulin, so TZDs are not indicated in type 1 diabetes or insulinopenic type 2 diabetes. TZDs, when used as monotherapy, are effective in reducing HbA1c. 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. About 25% of patients do not respond to initial therapy. 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.

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. 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 monotherapy is that hypoglycemia does not occur 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 act in the intestine to inhibit the action of alpha-glucosidase enzymes, which are responsible for breaking down complex carbohydrates into monosaccharides. Clinically, therefore, these agents reduce the postprandial excursion of blood glucose. They are not thus used for primary monotherapy unless a patient with mild fasting hyperglycemia appears to have large postprandial increases in blood glucose but are most useful in combined therapy. Gastrointestinal side effects are common, affecting up to 30% of patients. Bloating, flatulence, diarrhea and abdominal discomfort and pain can be reduced by eating less carbohydrate. If a patient develops low blood glucose levels, treatment must be with glucose rather than complex carbohydrates which will be unable to rapidly correct blood glucose. Weight gain does not occur with these agents.

Combination therapy

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 glucose control, i.e., a HbA1c of <7%. If treatment with one oral agent fails to achieve this goal, the following steps are recommended:

(A) Evaluate the non-medication regimen. Reevaluate the role of diet, exercise and education. Ask the patient to bring the failed drug into the office for visual confirmation and do standard questioning occurs about dosage and timing.

(B) Add another medication. (i) Add an insulin secretagogue if this has not been used as primary therapy. This can be added to metformin. (ii) 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. (iii) 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:
(A) Evaluate the non-medication regimen. A diabetes educator should determine the need and extent of this evaluation but it should not be ignored.
(B) 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:
(i) 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.
(ii) 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.
(iii) Patient's wishes regarding choice of therapy (insulin versus a second or third oral agent).
(iv) Other concomitant diseases (e.g., renal disease will affect the use of metformin, liver disease the use of thiazolidinediones).
(v) 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).
(vi) 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. 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. It may be useful as primary therapy once it appears on the market.

If you would like to read the full text of this article and review the associated CME questions, click here

Please note: You will first have to register on the Cyberounds site. If you are not yet a member, please just click here