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DOI: 10.1177/0145721706294260 © 2006 American Association of Diabetes Educators; Published by SAGE Publications
Practical Review of Oral Antihyperglycemic Agents for Type 2 Diabetes MellitusFrom the College of Pharmacy, Ferris State University, Upper Peninsula Health Education Corporation, Marquette, Michigan. Correspondence to Renee Rae Koski, PharmD, Ferris State University, UPHEC, 418 West Magnetic Street, Marquette, MI 49855.
This article gives a practical review of the pharmacology, clinical efficacy, safety, dosing, cost, and place in therapy for oral antihyperglycemic agents used in the treatment of type 2 diabetes mellitus. There are 5 classes of oral antihyperglycemic agents available in the United States: sulfonylurea secretagogues, biguanides,  -glucosidase
inhibitors, thiazolidinediones, and nonsulfonylurea secretagogues. These
agents have distinct characteristics that help in their selection for the
treatment of type 2 diabetes.
Diet, exercise, oral antihyperglycemic medications, and insulin are the mainstay of treatment of type 2 diabetes mellitus (T2DM). Oral agents are used in people who fail to meet glycemic goals with medical nutrition therapy and exercise. Insulin is usually reserved for those who fail or cannot tolerate oral therapy. People with T2DM have insulin resistance, impaired insulin secretion, and/or increased hepatic glucose production. Oral drug treatment to date is aimed at 1 or more of these defects. The purpose of choosing the appropriate agent(s) for a person is to increase the likelihood of getting their fasting plasma glucose (FPG) and A1C to the desired glycemic goal. This article reviews the 5 oral antihyperglycemic drug classes (sulfonylurea secretagogues, biguanides, -glucosidase inhibitors, thiazolidinediones,
and nonsulfonylurea secretagogues) available in the United States with respect
to mechanism of action, clinical efficacy, lipid effects, side effects,
significant drug interactions, dose, cost, and place in therapy.
Sulfonylureas have been available since 1954 and are classified as either first- or second-generation agents based on when they became available. The 2 generations differ in potency, safety, and pharmacokinetics. The second-generation agents are more potent and have better pharmacokinetic and safety profiles. The first-generation agents include acetohexamide (Dymelor®), chlorpropamide (Diabinese®), tolazamide (Tolinase®), and tolbutamide (Orinase®). The second-generation agents include glimepiride (Amaryl®), glipizide (Glucotrol®), and glyburide (Diabeta®, Micronase®, Glynase®). Sulfonylureas lower FPG primarily by increasing the release of insulin from functioning pancreatic ß cells. They display a glucose-dependent effect. Loss of efficacy over time is a major concern with the use of sulfonylureas. This appears to be related to exhaustion of ß-cell function. Sulfonylureas increase plasma levels of insulin and cause hypoglycemia. They reduce FPG by about 60 to 70 mg/dL (3.4-3.9 mmol/L) and A1C by 1.5% to 2.0% at maximally effective doses. Sulfonylureas do not have a significant effect on lipids.1 In the United Kingdom Prospective Diabetes Study (UKPDS), sulfonylureas were associated with a decrease in microvascular events compared to diet treatment, but there was no significant difference in mortality or macrovascular events. The lack of benefit on cardiovascular complications may be related to the fact that they cause hyperinsulinemia, which is associated with the metabolic syndrome.2 About 2% to 5% of patients report side effects with sulfonylureas.1 People started on a sulfonylurea should be counseled that hypoglycemia and weight gain (typically 4 to 6 kg) are the major adverse effects.2,3 Hypoglycemia is especially a problem with the first-generation agents because of their long half-lives. Elderly individuals, people who frequently skip meals, and people who perform frequent intense exercise are most susceptible. Given that there is a sulfonyl component in the chemical structure of sulfonylureas, hypersensitivity can occur in people with sulfa allergies and should be prescribed to people with a sulfa allergy with caution. There are drug interactions associated with sulfonylureas, including drugs that increase or decrease glucose or insulin (which would interact with all oral antihyperglycemic agents) and drugs that increase their renal excretion, increase or decrease their hepatic metabolism, or displace them from protein-binding sites.4 It is up to the clinician to decide which are clinically significant. Sulfonylureas should be started at low doses and titrated up every 1 to 4 weeks.1 Dose ranges for all oral antihyperglycemic agents are listed in Table 1. Most of the effect of sulfonylureas is usually observed with half the maximum daily dose.3 The significance of dosing oral antihyperglycemic agents up to their maximally effective dose (not their maximum daily dose) is for cost savings, avoidance of prolonged therapy that may not work, and more timely addition of another agent. Based on the results of the UKPDS, this class of drugs can be used as a first-line oral antihyperglycemic therapy, only when the person is not obese.
Metformin (Glucophage®) has been available since 1995 and is the only biguanide available in the United States. It is in the same drug class as phenformin, which was removed from the US and European markets in the 1970s because of its association with lactic acidosis.1 Metformin's primary mechanism for lowering FPG is to decrease hepatic gluconeogenesis. To a smaller extent, it also improves insulin sensitivity in peripheral tissues and decreases intestinal absorption of glucose. It does not affect insulin secretion, so it does not cause hypoglycemia. Metformin's effect may diminish over time. It is unclear why this may occur. It reduces FPG by about 60 to 70 mg/dL (3.4-3.9 mmol/L) and A1C by 1.5% to 2.0%, and it is glucose dependent.3,6 Metformin has been shown to decrease the low-density lipoprotein (LDL) levels and triglyceride levels (TGLs) by about 5 to 10 mg/dL (0.12-0.26 mmol/L) and has minimal effect on highdensity lipoprotein (HDL) levels.3,7 In the UKPDS and other more recent trials, a reduction in diabetes-related end points, deaths, and myocardial infarctions with metformin compared to diet therapy has been shown.2,8
About 20% to 30% of people on metformin experience gastrointestinal (GI)
side effects, such as nausea, metallic taste, abdominal discomfort, and
diarrhea, which can be minimized by titrating the dose up slowly and telling
patients to take it with
meals.1 A modest
weight loss has been associated with metformin. This weight loss is thought to
result from a reduction in net caloric intake due to appetite suppression
and/or a reduction in hyperinsulinemia related to insulin resistance. The
reported incidence of lactic acidosis with metformin is 0.03 per 1000
patient-years of use. It is fatal in 30% to 50% of
cases.9 A recent
systematic review found no cases of lactic acidosis associated with metformin
use in T2DM when contraindications were
followed.10 It is
contraindicated in people with the following risk factors for lactic acidosis:
renal (serum creatinine Metformin should be initiated at 500 mg orally twice daily, with the 2 largest meals of the day to minimize GI effects.11 Metformin XR should be started at 500 mg orally once daily with the evening meal, and beneficial effects can be seen within 1 week. The dose can be titrated every 2 weeks up to 2000 mg daily.1 Based on the UKPDS and clinical practice, metformin is considered a first-line agent and seems to be especially useful in a person who is obese or has known insulin resistance.
The -glucosidase inhibitors have been available since 1996 and
include acarbose (Precose®) and miglitol (Glyset®). These drugs slow
the rate of carbohydrate absorption in the small intestine, which results
primarily in a reduction in postprandial plasma glucose levels. They act as
competitive, reversible inhibitors of -glucosidase (found in the small
intestine) and -amylase (found in the pancreas), which convert
nonabsorbable dietary starch and sucrose into absorbable glucose and hydrolyze
complex starches, respectively. These agents do not affect insulin levels, so
they do not cause hypoglycemia when used alone. When -glucosidase
inhibitors are used with another antihyperglycemic agent (ie, sulfonylureas)
and hypoglycemia occurs, the hypoglycemia needs to be reversed by ingesting
glucose (tablets or gels), not complex carbohydrates. Complex carbohydrates
would be slowly broken down by the -glucosidase inhibitor and thus
would not be effective in quickly relieving hypoglycemia. FPG is reduced about
20 to 30 mg/dL (1.1-1.7 mmol/L) and A1C by 0.7% to 1.0%, and these agents are
more effective at lowering postprandial than preprandial glucose levels since
they are dosed with meals and have a short onset/offset. Postprandial glucose
levels are decreased by about 40 to 50 mg/dL (2.2-2.8 mmol/L), and no
significant effects on lipids have been
shown.1,12
Dosing should be initiated at 25 mg orally once or twice daily with the first bite of meals and titrated up every 2 to 4 weeks to a maximum dosage of 100 mg 3 times daily. If a meal is skipped (or added), the dose for that meal should be skipped (or added).13,14 These agents are useful for people with high postprandial glucose levels and/or irregular meal schedules.
Thiazolidinediones (TZDs) have been available since 1997 and include pioglitazone (Actos®) and rosiglitazone (Avandia®). TZDs act primarily to improve insulin sensitivity of muscle and adipose tissue. To a lesser extent, they decrease hepatic glucose production. TZDs are selective and potent agonists for the peroxisome proliferator-activated receptor  (PPAR) nuclear receptors. Activation of these receptors
regulates the transcription of insulin-responsive genes involved in the
control of production, transport, and use of glucose. The action of these
agents requires the presence of
insulin.3 TZDs may
also improve ß-cell function by reducing free fatty
acids.15 They do
not directly affect insulin secretion, so they are not associated with
hypoglycemia. TZDs' effects are glucose dependent, and they reduce FPG by
about 35 to 40 mg/dL (2.0-2.2 mmol/L) and A1C by 1% to
1.5%.1,16
They differ in their effects on lipids. Rosiglitazone increases LDL by 13 to
18 mg/dL (0.34-0.47 mmol/L), has no effect on TGL, and increases HDL by 2 to
3.4 mg/dL (0.05-0.09 mmol/L). Pioglitazone has a neutral effect on LDL,
decreases TGL by 26 to 53 mg/dL (0.29-0.60 mmol/L), and increases HDL by 3.61
to 5.48 (0.09-0.14
mmol/L).16 Both
agents may reduce the level of small, dense LDL cholesterol, which is thought
to be the most atherogenic lipoprotein component in people with diabetes and
may reduce macrovascular morbidity and
mortality.17-19
There are other PPAR agonists in early developmental stages that may have
improved lipid effects and less adverse effects compared to the current
agents.20 TZDs are associated with edema and weight gain (about 2 kg). The weight gain may be due to a change in fat distribution with an increase in subcutaneous adipose fat and a decrease in visceral fat. It could also be due to an increase in plasma volume (ie, edema). The edema is thought to be due to a decrease in renal excretion of sodium and an increase in sodium and free water retention. Pedal edema occurs in 3% to 5% of people taking TZDs. The incidence is greater when they are used with other glucose-lowering agents. Because of the edema, TZDs are contraindicated in people with New York Heart Association class 3 or 4 heart failure.21 The increase in plasma volume can also cause dose-related dilutional anemia (decreased hemoglobin of about 1 g/dL [0.62 mmol/L], hematocrit about 3.3%).1,21 There are rare postmarketing reports of new or worsening macular edema in people taking TZDs, and in some cases, improvement was seen with discontinuation of the drug. Most of these people also reported concurrent peripheral edema.22 TZDs can induce ovulation in women with polycystic ovary syndrome.4 Premenopausal and perimenopausal women with polycystic ovary syndrome must be made aware of this possibility. Pioglitazone and rosiglitazone have been associated with an increase in aspartate aminotransferase and alanine aminotransferase greater than 3 times the upper limit of normal at an incidence similar to placebo (0.25%). Troglitazone (Rezulin®) was taken off the US market in 2000 because of reports of idiosyncratic hepatocellular injury.23 Pioglitazone and rosiglitazone do not share this hepatotoxic profile; however, these agents should be used with caution in hepatic impairment. People on TZDs should have their liver enzymes monitored at the start of therapy and then annually thereafter. If a person's alanine aminotransferase level remains elevated above 3 times the upper limit of normal, the TZD agent must be discontinued.24,25 Pioglitazone is initiated at 15 mg orally daily and titrated up every 3 to 4 weeks to a maximum dose of 45 mg. Rosiglitazone's starting dose is 4 mg once daily or 2 mg twice daily and is titrated up at the same interval as pioglitazone to a maximum of 8 mg/d. TZDs have a slow onset of action, so the full effect may not be seen for up to 4 months.1 People with known insulin resistance and/or a contraindication to metformin may find TZDs of benefit.
The nonsulfonylurea secretagogues (available since 1998) include repaglinide (Prandin®) and nateglinide (Starlix®).1 Mitiglinide is available in Japan. It is in phase 3 trials in Europe and in phase 2 trials in the United States.26 These agents stimulate the release of insulin from functioning pancreatic ß cells if glucose is present. Repaglinide and nateglinide reduce FPG by about 65 to 75 mg/dL (3.6-4.2 mmol/L) and A1C by about 1.5% to 2.0% and 0.5% to 1.5%, respectively.1,27,28 They have a short half-life, so they stimulate insulin release for brief episodes. The quick on and off helps decrease hypoglycemia, hyperinsulinemia, weight gain, and possible ß-cell exhaustion compared to sulfonylureas. Dosed prior to meals, the maximal effect on glucose occurs postprandially. Meglitinides have no effect on lipids. Both agents are metabolized by CYP 450 3A4, and nateglinide is also metabolized by 2C9.1,4 Repaglinide should be initiated at 0.5 mg 3 times daily orally and titrated up to a maximum daily dose of 16 mg.29 Most of the benefit is achieved with 1 mg 3 times daily.1 Nateglinide should be initiated at 60 mg 3 times daily orally and titrated up to a maximum daily dose of 360 mg.30 Doses should be taken 15 to 30 minutes prior to meals. If a meal is skipped (or added), the dose for that meal should be skipped (or added).29,30 These agents are useful for people with high postprandial glucose levels and/or irregular meal schedules.
If monotherapy does not achieve goal glycemic levels, combination therapy is used. Most of the drug classes reviewed can be combined, except sulfonylureas and non-sulfonylurea insulin secretagogues since they have the same mechanism of action. There are combination tablets that have been formulated to allow for a decreased pill burden (see Table 1). If combination oral therapy does not achieve glycemic goals, insulin should be initiated. There are several reasons people may fail monotherapy. First, results from the UKPDS showed that sulfonylureas and metformin are efficacious for approximately 5 years; after that, people require a change or addition in their therapy. At 3 years, 50% of the people in the UKPDS achieved glycemic goals with monotherapy. At 9 years, only 25% were at goal with monotherapy. The conclusion was that because diabetes is a progressive disease, most people need multiple therapies to continue to attain glycemic goals.31 Also, failure of monotherapy occurs because of noncompliance. This may be because of a lack of knowledge about medications, adverse effects, cost of obtaining the medications, or other reasons. In a study in 2000, 261 people with T2DM from the United Kingdom were surveyed about their knowledge of their oral antihyperglycemic agents. Findings included that (1) 62% took their medication correctly in relation to food, (2) 10% of those taking sulfonylureas knew it may cause hypoglycemia, (3) 20% of those taking metformin were aware of its GI side effects, (4) 35% recalled receiving advice about their medication, (5) 20% forgot to take their medication at least once a week, and (6) 5% omitted doses because of hypoglycemia.32 This is an important reminder to educate people with T2DM about the proper use of oral antihyperglycemic drugs.
There are new classes of oral drugs in early stages of development for the treatment of T2DM, including DPP-IV enzyme inhibitors and glucokinase (GK) activators.33,34 DPP-IV is responsible for cleaving certain polypeptides. Inhibiting this enzyme results in decreased FPG and suppression of postprandial glucose excursions. On February 21, 2006, Merck & Co, Inc announced that the new drug application (NDA) for its once-daily DPP-IV enzyme inhibitor, Januvia® (sitagliptin phosphate), was accepted for standard review by the US Food and Drug Administration (FDA). Merck expects FDA action on the NDA by mid-October. Januvia® would potentially be the first in a new class of oral medications (DPP-4 inhibitors) that enhances the body's own ability to lower blood sugar when it is elevated.35 GK is present in pancreatic ß cells and acts as a glucose sensor to establish the threshold for glucose-stimulated insulin release. GK is also present in the liver. It controls hepatic glucose metabolism and influences glucose uptake and production. Mutations of the GK gene result in several subtypes of diabetes. Drugs that activate GK would be a novel approach to the treatment of T2DM since it is involved in glucose homeostasis.34
T2DM is a chronic disease that usually requires drug therapy. All of the available oral antihyperglycemic agents are effective at lowering plasma glucose and A1C levels. Choosing the oral antihyperglycemic agent(s) that best fits the individual person and educating them on the proper use of the medication will enhance efficacy, safety, and compliance with therapy.
No financial support was received for preparation of this article. I would like to thank Joan Rider, PharmD, BCPS, CDE, for reviewing this article.
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Abstract
Sulfonylurea Secretagogues
1.5 mg/dL [132.6 µmol/L] in men or