Nateglinide (Starlix®)
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Volume IV, Number 2 | March/April 2001

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Hyperglycemia is the major contributor to both the acute and chronic complications of diabetes mellitus (DM). Several studies, including the Diabetes Control and Complication Trial (DCCT), showed that microvascular disease such as retinopathy, nephropathy, and neuropathy are strongly related to poor glycemic control. Hyperglycemia may also be a risk factor for macrovascular disease.

Data show that average blood glucose, expressed as HbA1c, may predict the risk of coronary heart disease morbidity and mortality. The lowest morbidity and mortality are observed at HbA1c < 6% while the highest rates are at levels
> 7.9%.

Evidence of coronary heart disease associated with hyperglycemia, particularly postprandial glucose levels, were found in both the Honolulu Heart Study and Islington Diabetes Survey. Therefore, therapies that focus on lowering postprandial glucose may be beneficial.

Recently, nateglinide (Starlix®) received FDA approval as monotherapy or in combination with metformin (Glucophage®) for Type 2 diabetes in patients whose hyperglycemia can not be controlled with diet and exercise.

Nateglinide lowers blood glucose by stimulating the release of insulin from the pancreatic beta cells by binding to receptors that block potassium-ATP channels. This causes depolarization of the cells which therefore activates voltage-dependent L-type calcium channels and increases intracellular calcium, thus leading to insulin release.

Due to its rapid absorption and clearance, nateglinide has a rapid onset of action and shorter duration of effect. Nateglinide's effect on insulin release occurs within 20 minutes and returns to baseline after 1.5 hours with the peak level lasting approximately one hour. Its half-life is approximately 1.5 hours. About 16% of the dose appears unchanged in the urine. Nateglinide is extensively bound to serum protein (99%), primarily serum albumin. The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent than nateglinide. Nateglinide is metabolized predominantly by cytochrome P450 2C9 and 3A4.

Nateglinide appears to be well tolerated. Adverse effects have included symptoms similar to mild hypoglycemia (increased sweating, dizziness, tremor), increased appetite, asthenia, headache, fatigue, upper respiratory infection, and diarrhea. Increased liver function tests and uric acid levels have also been reported.

Nateglinide is contraindicated in patients with known hypersensitivity to the drug or its inactive ingredients, Type 1 diabetes, or diabetic ketoacidosis.

There have been no significant drug interactions documented in studies between nateglinide and glyburide, metformin, digoxin, or diclofenac. There have also been no documented interactions with highly protein bound drugs. Blood glucose levels should be monitored closely when adding nateglinide to any regimen that can affect blood glucose levels such as beta-blockers, thiazides, corticosteroids, NSAIDs, and sympathomimetics.

It may be added to, but not substituted for metformin. Patients whose hyperglycemia is not adequately controlled with glyburide or other agents that increase the secretion of insulin, should not be switched to nateglinide, nor should nateglinide be added to their current drug regimen. Both nateglinide and sulfonylureas act on beta cells in the pancreas therefore, if there is no response to a sulfonylurea there most likely will not be a response to nateglinide.

For monotherapy and in combination with metformin, the recommended starting and maintenance dose of nateglinide is 120 mg administered orally three times daily 30 minutes before meals. A lower dose of 60 mg administered orally three times daily alone or in combination with metformin may be given to patients whose HbA1c values are near goal.

Dosage adjustments are not necessary in the elderly or in patients with mild to severe renal impairment.

Nateglinide should be used with caution in patients with chronic liver disease. The safety and effectiveness of nateglinide in pediatric patients have not been established.

Nateglinide is available as 60- and 120-mg tablets. The average wholesale price (AWP) is $0.92 and $0.96, respectively. A total daily cost for 60 mg three times a day is $2.76 and for 120 mg three times a day is $2.88.

Nateglinide is a new oral antidiabetic agent, designed to prevent postprandial hyperglycemia. It is indicated for use as both monotherapy and in combination with metformin, in patients whose blood glucose is not controlled by diet and exercise. Since nateglinide does not cause late hyperinsulinemia due to its rapid onset of action and short duration of effects, the risk of hypoglycemia can be reduced. When combined with metformin, nateglinide may control postprandial glucose more effectively than either agent alone which can prevent long-term complications associated with diabetes.

Nateglinide is not effective for patients who have failed oral sulfonylurea therapy. Its advantages over sulfonylureas include a more rapid onset of action as well as a shorter duration of effect.

The patients that are best suited for therapy with nateglinide include 1) newly diagnosed patients after non-pharmacological measures have not controlled blood glucose and 2) patients in need of better control with metformin. Patients should be advised not to miss meals and to maintain adequate food intake if engaging in strenuous exercise to avoid the risk of hypoglycemia.

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Copyright © 2000-2021 The Cleveland Clinic Foundation. All Rights Reserved.
Center for Continuing Education | 1950 Richmond Road, TR204, Lyndhurst, OH 44124