Drug Profile

Repaglinide (PRANDIN) and nateglinide (STARLIX) are members of the family of diabetes drugs known as meglitinides (also called glinides). Repaglinide was approved by the Food and Drug Administration (FDA) in December 1997 and nateglinide in December 2000.

Both nateglinide and repaglinide work in a manner similar to the oldest class of diabetes drugs, the sulfonylureas — for example, glipizide (GLUCOTROL) — by stimulating the release of insulin from cells in the pancreas.

We recommend that you do not use these drugs because they have a similar risk of weight gain as sulfonylureas and less is known about their safety risks relative to older classes of diabetes drugs. Nateglinide is also less effective at lowering blood sugar.

These two drugs are approved for use only when elevated blood sugar levels cannot be controlled satisfactorily with diet and exercise alone.

Both drugs can be used in combination with metformin (GLUCOPHAGE), a member of the biguanide class of diabetes drugs.

In considering the use of oral diabetes drugs, it should be recognized that only blood sugar control using diet, insulin or some older drugs has been shown to delay the long-term complications to the eyes, nervous system and kidneys that can occur with type 2 diabetes. The picture is not as clear in regards to the effect of any oral antidiabetic drugs on controlling blood sugar and the cardiovascular complications of diabetes, such as heart attacks and strokes, even though there is some evidence that coronary heart disease and high blood sugar levels are linked.

The product labeling for nateglinide suggests that the drug is minimally effective in lowering blood sugar and another measure of diabetes control, hemoglobin A1c (HbA1c) blood levels. A study described in the labeling found a negligible effect on blood sugar and HbA1c levels even at the drug’s highest recommended dose.[1] These results were statistically significant in favor of nateglinide, but, as is often the case with new drugs, the clinical effect was insignificant.

Another clinical trial summarized in nateglinide’s labeling involved patients whose blood sugar was not controlled after treatment with a sulfonylurea. In this study, the effect of nateglinide was compared with that of the sulfonylurea glyburide (DIABETA). Patients switched to nateglinide had significant increases in their average blood sugar and HbA1c levels compared with those taking glyburide, thus worsening their diabetes control.

The editors of The Medical Letter on Drugs and Therapeutics reviewed nateglinide in April 2001. Their conclusion was, “Nateglinide is a short-acting hypoglycemic agent that is less convenient and less effective than a sulfonylurea and much more expensive. Its long-term safety remains to be established.”[2]

The drug companies attempted to create a “hook” to sell repaglinide and nateglinide by making it seem that, despite their less-convenient three-times-daily dosing requirements, these drugs are a novel advance in the treatment of type 2 diabetes. The spin went like this: There is a better correlation between the risk of cardiovascular disease from diabetes and blood sugar levels after eating than there is for fasting blood sugar levels (one of the blood tests usually performed to monitor diabetes treatment). It is thus implied that targeting elevated blood sugar levels after eating reduces cardiovascular risk, which can be accomplished by using meglitinides because they have a rapid onset of action and must be taken three times a day.

A physician who took money from Novo Nordisk and Novartis played up the “benefits” of treating post-eating blood sugar levels in the medical journal The Lancet.[3] She was quickly taken to task in a Jan. 12, 2002, letter to the editor of The Lancet that emphasized that “no data yet support postprandial glycaemia [elevated blood sugar after eating] as a therapeutic target for cardiovascular risk reduction.”[4] The letter pointed out that this is a misleading claim made by manufacturers of the meglitinide diabetes drugs.

The European Agency for the Evaluation of Medicinal Products (EMEA) — now called the European Medicines Agency, an agency similar to the FDA — issued a public warning on May 21, 2003, not to use the combination of repaglinide and the cholesterol drug gemfibrozil (LOPID). The basis for the EMEA warning was a publication in the March 2003 issue of the medical journal Diabetologia that found the use of these two drugs in combination can enhance the blood-sugar-lowering effects of repaglinide and can thereby result in severe blood sugar decreases (hypoglycemia). The Europeans have received five reports of serious hypoglycemia associated with the use of repaglinide and gemfibrozil.[5],[6]

In 2015, Health Canada (an agency similar to the FDA) issued an advisory that repaglinide and anti-platelet drug clopidogrel (PLAVIX) should never be taken together because the combination may lead to hypoglycemia (low blood sugar levels).[7]

In 2016, Public Citizen petitioned the FDA to require that the product labeling for repaglinide be revised to include a warning about the risk of dangerously low blood sugar levels when it is taken together with the anti-platelet drug clopidogrel. In 2017, the FDA approved changes to the product labeling for both repaglinide and clopidogrel indicating that this drug combination should be avoided.[8]

The product labeling for repaglinide also warns against combining repaglinide with NPH insulin because the combination may increase the risk of adverse cardiovascular events, including heart attacks.[9]