VDC - Diabetes Toolbox

Week of March 4, 2005

Oral Agents in the Treatment of Diabetes

Oral agents are useful only for patients with type 2 diabetes and/or insulin resistance. The overarching goal of all diabetes therapy is to achieve chronic glycemic levels as close to the non-diabetic range as is safely possible. The goal selected for an individual patient should be determined by risk: benefit considerations that recognize the patient’s age, projected life-span and preferences along with recognition of effort required and cost. While the following is not an exhaustive nor complete review of the use of oral agents in the care of diabetes, it serves to summarize important considerations about each available class of agent and may assist providers in choosing appropriate therapy.

Metformin (Glucophage) enhances insulin action but does not stimulate insulin secretion. Metformin is generally considered the first choice oral agent in many circumstances, especially for patients who are overweight; it is the only widely used, well-tolerated glucose lowering medication (oral agent or insulin) that does not promote weight gain. Metformin may induce GI symptoms that are generally modest, often resolve within the initial 1 – 3 weeks of use and infrequently require its discontinuation; it is best tolerated when initiated at a low dose with gradual dose escalation over the course of several weeks. The usual decline in HbA1c levels induced by metformin use is 1 – 2%. Metformin can be used in combination with insulin or other oral agents with synergistic effect. Long-acting metformin preparations are more expensive and generally not preferred, however may be better tolerated when GI symptoms are problematic. Unlike sulfonylureas, metformin generally does not cause hypoglycemia when used as monotherapy. Lactic acidosis, a potentially fatal adverse effect of metformin is extremely rare when the medication is avoided among patients at risk (those with renal dysfunction, congestive heart failure or other conditions that predispose the patient to lactic acidosis). When used in obese subjects in the UKPDS, metformin was associated with reduced macrovascular risk. When combined with sulfonylureas, however, metformin was associated with an increased mortality.

Sulfonylureas (glyburide (Micronase and Diabeta), glipizide (Glucotrol), glimeperide (Amaryl) and others) stimulate beta cell insulin secretion. Sulfonylureas have been available for a number of decades, are relatively inexpensive, and lower HbA1c levels by 1 – 2%. Some diabetologists at the MGH and elsewhere tend to avoid sulfonylureas due in part to the findings of the UGDP performed in part at the MGH in the late 1960s suggesting an increase in mortality among patients with myocardial infarction with sulfonylurea use; sulfonylureas may also hasten beta cell failure in type 2 diabetes. Glimeperide (Amaryl) is promoted as less likely to inhibit cardiac ischemic preconditioning, and on that basis, may (or may not) have less of a cardiac adverse effect than other sulfonylureas. Sulfonylureas should be used with caution in the setting of renal insufficiency (see below), and one should be aware that hypoglycemia, when induced, may be prolonged. These agents are less commonly used than insulin sensitizers (metformin and TZDs) in combination with insulin.

Meglitinides (nateglinide (Starlix), repaglinide (Prandin)) are non-sulfonylurea insulin secretagogues and, are therefore similar to sulfonylureas, although shorter acting. They must be taken before meals to promote meal-stimulated insulin release and therefore limit post-prandial hyperglycemia. Meglitinides reduce HbA1c levels by 1 – 1.5%, require frequent dosing, and are not available as generics. They should not be used in combination with sulfonylureas.

Thiazolidinediones (TZDs - pioglitazone (Actos), rosiglitazone (Avandia)) enhance cellular glucose uptake in response to insulin, thus acting as insulin sensitizers. Unlike metformin, TZDs promote weight gain. TZDs may provide certain benefits relative to cardiac risk through improvement in vascular endothelial function and coagulation parameters, lowering of hsCRP and improvement in lipids. Despite that, there are no outcome studies demonstrating a lowering of cardiovascular morbidity or mortality. TZDs may promote edema and are contraindicated among patients with CHF or pre-existing edema. TZDs have a slow onset of effect in glucose lowering, requiring approximately 3 weeks to be successful and then lower HbA1c levels by only 0.5 – 1% when used as monotherapy; they may be more useful in combination with insulin, metformin or a sulfonylurea.

Alpha-glucosidase inhibitors (AGIs - acarbose (Precose) and miglitol (Glyset)) reduce the intestinal conversion of oligosaccharides and disaccharides to monosaccharides resulting in slowed carbohydrate absorption. AGIs will therefore inhibit post-prandial hyperglycemia. These agents tend to cause a high level of GI intolerance, particularly causing flatulence, and are often poorly tolerated. These agents are taken before each meal, and lower HbA1c levels by only 0.5 – 1.0%.

- Special Populations -

Overweight patients – Metformin and AGIs are the only agents that don’t promote weight gain. Metformin is generally considered the first choice oral agent given its long history of use, effectiveness in lowering HbA1c levels and safety/tolerability profile.

Thin patients – Often have insulin deficiency rather than insulin resistance, and will generally need to move toward insulin more quickly as a result. Metformin is more effective than sulfonylureas in this setting.

Renal insufficiency – Metformin is contraindicated if creatinine is ≥ 1.4 among women, ≥ 1.5 among men due to risk of lactic acidosis (see additional caveat below regarding older patients). Of the oral agents, the glitinides are probably the safest since they have no renal clearance.

Cardiac disease, CHF – TZDs promote fluid retention and may promote CHF, and are therefore avoided if CHF (or CHF risk) is present. Metformin is contraindicated when renal function is compromised or renal hypoperfusion is present, or if CHF is sufficiently severe so as to pose a risk of hypoperfusion and lactate accumulation. As mentioned, some diabetes experts avoid sulfonylureas, particularly when cardiovascular disease is present. Given these concerns insulin may be preferred, particularly when active CHF is present.

The elderly – Given that the benefit achieved from favorable blood glucose control accrue over a long-term horizon, therapeutic goals should at times be modified in light of projected lifespan. Caution is also recommended given an increase in risk associated with hypoglycemia, noting that the elderly are felt by some to have a greater likelihood of hypoglycemia unawareness. Metformin dose should be considered carefully, given that serum creatinine may not fully reflect renal function with advancing age; metformin should not be titrated to the maximum dose and should be held for a creatinine clearance < 60 ml/min. Sulfonylureas should be given with increased caution as well, particularly those with longer duration of action (e.g. chlorpropamide, glyburide and possibly glimeperide) given associated hypoglycemia risk; glipizide and particularly the meglitinides may therefore be preferred.

This review was created by the Partners Diabetes Council, a multidisciplinary 35 member body created by Signature Initiative 3 (Uniform High Quality). The PDC seeks to enhance diabetes care throughout the Partners community, focusing on clinical information systems and on provider and patient education and support. To access the Diabetes Council, contact Alan Cole, M.D. or Lisa Gintner.

See the supplement focus sheet for pricing and tier information on the medications discussed located on PCHInet.