Drugs for Prediabetes   (August 22, 2010)

Someone recently asked about taking Actos (pioglitazone) for insulin resistance; they indicated that they don't "yet" have diabetes. The question opens up a huge can of worms about off-label use of medications, especially diabetes medications.

"Off-label use" should be defined before we go any further: off-label use refers to the use of a prescription drug for an indication that isn't in the official prescribing information that has been approved by the FDA or other regulatory agencies in other countries. So, for instance, if you read the label for exenatide (Byetta), you'll read a statement that "The concurrent use of BYETTA with insulin has not been studied and cannot be recommended." Therefore, taking Byetta with insulin is "off-label." Interestingly, if you go to ClinicalTrials.gov, you'll find a study being carried out by the manufacturer of Byetta, comparing insulin plus exenatide and metformin therapy to a program without Byetta.

And to make things even more interesting, it's quite possible that what's approved by the FDA for a manufacturer to claim in their drug label may not be approved by European health authorities for the European version of the label for the same product (and vice versa).

Back to the writer's question, and one of my own: what drugs are approved for use in prediabetes? None.

But if we revise my question a bit, and say "what drugs have been studied in patients with prediabetes?" we can find numerous such studies.

Metformin
Metformin has been extensively studied "off-label" for people with prediabetes (just go to ClinicalTrials.gov, and plug in "metformin" and "prediabetes" in the search box to see a list of such studies). The biggest of the studies of metformin in prediabetes was probably the Diabetes Prevention Program (DPP), which showed that diet and exercise sharply reduce the chances that a person with prediabetes would develop diabetes. Metformin also reduced risk, although less dramatically.

Exenatide
Exenatide also is undergoing study in patients with prediabetes: plug in "exenatide" and "prediabetes" at ClinicalTrials.gov

Insulin
"ORIGIN" is a huge trial (with 12,500 patients) using Lantus (insulin glargine) in patients with prediabetes or type 2 diabetes.

Thiazolidinediones ("glitazones")
There are three glitazone drugs that have been marketed. The first, troglitazone (Rezulin) was studied off-label in the Diabetes Prevention Program and other studies; the other two (rosiglitazone/Avandia) and pioglitazone/Actos) have been extensively studied in prediabetes.

DPP-4 inhibitors ("gliptins")
There are three DPP-4 inhibitor drugs that have been marketed, sitagliptin (Januvia), saxagliptin (Onglyza), and vildagliptin (Galvus, which is approved in Europe but not in the United States). Again, ClinicalTrials.gov shows studies with sitagliptin and vildagliptin, but not with saxagliptin.

Thus it appears that the manufacturers are very interested in seeing the effects of their drugs on a population of patients with prediabetes - a population that to date has no medications approved to treat. Perhaps they will do sufficient studies to persuade the FDA to add another indication to the list; having  an indication for "prevention of diabetes" could be a financial blockbuster.

But until such studies are complete, and the FDA is content with the efficacy and safety of these drugs in prediabetes, it's entirely up to each patient's physician as to whether to prescribe one or another of these drugs for patients who don't yet have type 2 diabetes. In theory, they should help in patients with prediabetes, and several would help diminish insulin resistance. Indeed, the DPP shows that metformin does indeed help

Whether the good things these drugs might do (such as decrease insulin resistance and delay the onset of type 2 diabetes) outweighs the bad things that might occur (such as gastrointestinal side effects and the rare risk of lactic acidosis with metformin, and the drain on the patient's pocketbook as insurance will probably not cover off-label use) is an individual decision based on the individual's medical history and tolerance of risk.

I think any patient contemplating using medications to prevent type 2 diabetes should sign up for a study that's recruiting such patients, or have a long talk with their physician about whether such medication would be appropriate for them.