Oral Agents for Lowering Blood Sugar in Type 2 Diabetes

Author’s note: Throughout this series, I will inject my own opinion, which frequently differs from that of the medical establishment in this field. Having had diabetes for more than 66 years, I place my emphasis on the well-being of fellow patients.

There are currently eight categories of oral agents marketed in the US for lowering blood sugar in type 2 diabetes. Each category has different reasons for use, differing efficacies for different individuals, different potential adverse effects, and possibly different off-label applications for purposes other than blood sugar control.
Before I begin to discuss these agents, I must point out three facts that are frequently overlooked in conventional medical practice:

  • Far more effective for reducing blood sugars than any of these medications is adherence to a very low-carbohydrate diet. The effect of these products on lowering blood sugar is easily overwhelmed by the effect of dietary carbohydrate on raising it.


  • Injected insulin is the most potent blood-sugar-lowering medication we have. Furthermore, it always works. For this reason, most of my type 2 patients are obliged to inject insulin (in addition to possibly taking oral agents) if they want truly normal blood sugars around the clock (about 83 mg/dL for adults, and an A1C of 4.2% to 4.6%). Many physicians avoid the use of insulin, however, because they do not know how to safely adjust doses of this potent hormone.


  • Diabetes is much easier to control if as many pancreatic beta cells (which make insulin) as possible are preserved. Therefore, an important goal of treatment should be beta cell preservation. This is most readily accomplished by absolute normalization of blood sugar from the first sign of impaired glucose tolerance. In the 1980s, Gerald Reaven actually demonstrated partial beta cell recovery after keeping blood sugars normal with the assistance of a mechanical pancreas. I have subsequently seen this effect in my own patients with the help of diet and injected insulin. A recent study from Korea again duplicated these results, as did another recent study in the US.

Sulfonylurea Agents

The sulfonylureas are the second oldest of the oral agents approved by the FDA for lowering blood sugars. They include glipizide (Glucotrol), glyburide (Micronase), and glimepiride (Amaryl), as well as the older drugs tolazamide (Tolinase) and chlorpropamide (Diabinase).

With the exception of timing of action after administration, all these drugs (pills) are approximately equivalent. They share similar potency at the recommended doses, similar benefits, and similar adverse effects. They all work by stimulating the beta cells of the pancreas to make more insulin. The more healthy beta cells a person with diabetes has, the more insulin will be produced.

For those of us who have many functioning beta cells, sulfonylureas and meglitinides are by far the most potent oral agents we have. There is a catch, however. The blood sugar effect depends on the dose administered, not on the actual blood sugar–just like injected insulin. These drugs, therefore, do not automatically keep blood sugars at the level we desire. It is possible for blood sugar to go dangerously low (hypoglycemia) if the user is not very careful about adhering to a fixed meal plan and frequently measured blood sugars. It is not a matter of taking a pill and forgetting about everything else–even though that is often the approach to treatment.

The most rapid acting of the sulfonylureas is glipizide. Onset of action begins for most users about 30 minutes after taking the pill, and it continues to work for several hours after administration. So, in principle, this drug is appropriate for preventing blood sugar rise after meals. It may not be totally effective for preventing the rise after eating high-carbohydrate meals, because carbohydrates can raise blood sugar faster than glipizide can lower it. A timed release version of glipizide, which is also on the market, has a much longer-acting effect that closely resembles the drugs described in the next paragraph.

Many people with type 2 diabetes find that their blood sugars increase even when they are not eating, as during an overnight fast or between meals. Glyburide, glimepiride, tolazamide, and chlorpropamide take longer to start working and have blood-sugar-lowering effects that last much longer than glipizide. It would thus be appropriate to take these drugs on arising and at bedtime to cover the fasting state.

Thirty years ago, before I became aware of the adverse effects of sulfonylureas, I used glyburide to cover the fasting state, together with glipizide before meals. The combination was very effective, provided users were on fixed, low-carbohydrate diets. Unfortunately, it took a few years for me to realize that these drugs were causing what I thought was destruction of beta cells. A recent study on mice appeared to show that they merely paralyzed beta cells so that the cells could no longer secrete insulin. This effect was reversed if the drugs were discontinued for a while. Another study showed that when beta cells were caused by the drugs to secrete insulin, the beta cells expressed unique proteins on their surfaces. These proteins can readily be attacked by our immune system, eventually causing beta cell destruction–just as I had originally hypothesized.

There is another major problem associated with sulfonylureas: Since 1970, repeated studies have found them to be associated with excess mortality from cardiac disease, independent of other risk factors such as high blood sugar. It appears that when these drugs facilitate insulin production by closing potassium channels in beta cells, they also close potassium channels in the muscles that relax arteries. As a result, the arteries constrict, and circulation (to the heart) is impaired. As recently as June 2012, a 24,000 person comparison of sulfonylureas with a totally different oral agent, metformin, showed a 59 percent to 68 percent greater all-cause mortality among the sulfonylurea users.

For some individuals, sulfonylureas can cause severe facial flushing after consuming alcoholic beverages. This phenomenon, called the “disulfuram effect,” is certainly not life-threatening. Sulfonylureas, along with the meglitinides described below, are the most potent of the oral drugs in terms of blood sugar lowering. This potency is probably the main reason for their popularity among physicians in spite of their adverse effects upon beta cells and cardiac mortality. They can make a physician’s life easier by enabling the avoidance of teaching insulin use–at least until beta cells stop functioning.

The Meglitinides

There are currently two newer medications on the market that work by pushing beta cells to make insulin by the same mechanisms as sulfonylureas. However, they are chemically different; for example, they do not cause the disulfuram effect. The two meglitinides, repaglinide (Prandin) and meglitinide (Starlix), are fast-acting and are typically taken before meals to reduce blood sugar rise after meals. Because their mode of action is so similar to sulfonylureas, I naturally fear both beta cell impairment and increased cardiac mortality–even though I haven’t seen any such studies of the meglitinides.

I last prescribed sulfonylureas in the late 1980s, and have deliberately refrained from prescribing meglitinides. Having diabetes myself, I cannot envision exposing fellow patients to the problems described above. There are, however, other oral agents for treating diabetes, which I do prescribe. They will be discussed in subsequent articles of this series.

Richard K. Bernstein, MD, FACE, FACN, FCCWS, has had type 1 diabetes for more than 66 years. His latest books include Diabetes Solution and Diabetes Diet, both published by Little Brown, and the e-book Beating Diabetes. He limits his medical practice in Mamaroneck, NY, to the treatment of diabetes and obesity.

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