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Glipizide, Gliclazide, Glyburide, Repaglinide, etc: Drugs that Stimulate Insulin Secretion


Among the oldest and cheapest drugs for diabetes are the drugs that force the beta cells to secrete insulin whether or not the blood sugar is high. There are two families of these drugs: the sulfonylurea drugs, which include Glyburide, Glimepiride, and Glipizide and the newer family of "glinide" drugs which include Stalix (natalinide) and Prandin (repaglinide).


The Sulfonylurea drugs are the most long lasting. They stimulate insulin production for 8-12 hours regardless of blood sugar level. The drugs in the sulfonylurea family include Amaryl (glimepiride), Glucatrol, (glipizide), Micronase (glyburide), and Diamicron (gliclazide). They bind to a ATP-dependent K+ (KATP) channel in the beta cell membrane, which causes the beta cell to steadily secrete insulin whether or not glucose is present in the blood stream. Because of this, these drugs are notorious for causing dangerous hypos.


This means that people who take these drugs are often told to keep their carbohydrate consumption high to avoid dangerous hypoglycemic episodes. Since our goal is to lower blood sugar, that rules these drugs out as useful tools since they require that patients maintain their blood sugar at levels far above 140 mg/dl in order to avoid hypos.


Most Sulfonylurea Drugs are Associated with Cardiac Risk

Glyburide and Glipizide, the older versions of the sulfonylurea drugs were been found to raise the incidence of heart attack. This is because they not only stimulate the beta cell, they also stimulate a receptor on the heart muscle. A study published in 2008 that quantified the heart attack potential of the various sulfonylurea drugs found that,


The hazard of developing CAD [coronary artery disease] associated with initial treatment increased by 2.4-fold ... with glibenclamide [glyburide]; 2-fold ... with glipizide; 2.9-fold ...with either, and was unchanged with metformin. The hazard decreased 0.3-fold ... with glimepiride, 0.4-fold ... with gliclazide, and 0.4-fold ... with either.


Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes: A matched case–control study Shaukat M. Sadikot et al. Diabetes Research and Clinical Practice. Volume 82, Issue 3, December 2008, Pages 391-395


There is already a black box warning in all sulfonylurea drugs sold in the U.S. warning of heart attack risk, but a recently published study came up with the finding that the more sulfonylurea a person took, the higher the risk for a cardiac "event (i.e. heart attack).


Do sulfonylurea drugs increase the risk of cardiac events?David S.H. Bell.CMAJ January 17, 2006; 174 (2). doi:10.1503/cmaj.051237.


Only Two Insulin Stimulating Drugs Are Safe

A study published in 2011analyzed the health records of "All Danish residents >20 years, initiating single-agent I[nsulin] S[ecretogogues, ie. Sulfs and glinides] or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years)." It found the following drugs were as safe as Metformin: Prandin (repaglinide), and Diamicron (gliclazide, not sold in the U.S.).


All the other sulfonylurea drugs raised the risk of death, whether or not people had had a heart attack before taking them.


The study concludes:


Monotherapy with the most used I[nsulin]S[ecretagogues]s, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other I[nsulin]S[ecretagogues]s.


Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Tina Ken Schramm et al. Eur Heart J (2011) doi: 10.1093/eurheartj/ehr077


And if that wasn't enough, a study of the records of over 250,000 veterans found that "...for every 1,000 patients who are using metformin for a year there are two fewer heart attacks, strokes or deaths compared with patients who use sulfonylureas."


Science Daily: Metformin Offers Cardio Benefits Over Sulfonylureas in Diabetes, Study Suggests


Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus: A Cohort Study Christianne L. Roumie, et al. Ann Intern Med. 6 November 2012;157(9):601-610


The Meglitinide Drugs, Starlix and Prandin, Have A Much Shorter Duration of Action

These two drugs also work on the ATP-dependent K+ (KATP) channel of the beta cell membrane, but at a different site. They have a half life within the body of 1-1.5 hours. So if taken with meals,they are less likely to cause hypos, though users of these drugs report that they are still capable of causing reactive low blood sugar attacks. My own experience with Prandin is that the brand name version it is much milder in its effect than a sulfonylurea drug and that its effect is much shorter--extending only through the couple hours that follow a meals. Prandin, now sold in the U.S. under the generic name, repaglinide appears to be safe for the heart.


Generic Repaglinide May Not Have the Same Speed of Action as Name Brand Prandin

By using a FreeStyle Libre Flash Glucose Monitor, I was able to see exactly how repaglinide works for me, and discovered that it appears to activate much more slowly than the brand name Prandin version that I used to use before the drug was available as a generic.


My pharmacist confirms this is likely. If your insurance will let your doctor prescribe the name brand version, use it. Otherwise, you may have to take repaglinide 1 to 2 hours before eating to get it to lower the peak caused by a meal. If you take it at meal time, as directed by the label, you may get a peak one hour after eating, followed by a potentially serious low an hour or two later. The branded version can be taken at mealtimes and peaks at 1 hour after it is taken.

The Glinide Drugs, Starlix and Prandin, May Also Raise GLP-1 by Inhibiting DPP-4

A study shows that these drugs appear to inhibit DPP-4, in a manner similar to Januvia. As we have explained in our discussion of DPP-4 inhibitors there is a chance this is a dangerous way to lower blood sugar, because DPP-4 has been found to be a tumor suppressor gene, so while inhibiting it does lower blood sugar, it also may allow cancer cells to proliferate.


The good news about Starlix and perhaps Prandin, is that because these drugs have a much shorter half-life in the body--1.5 and 1 hours vs 12.5 hours for Januvia, the suppression of DPP-4 may be short term and the tumor suppression may continue except for a few hours around meal time. Even so, because no research has been done to investigate the impact of inhibiting DPP-4 with diabetes drugs, this mechanism for lowering blood sugar is of unknown safety.


Effects of antidiabetic drugs on dipeptidyl peptidase IV [?] activity: nateglinide is an inhibitor of DPP IV [?] and augments the antidiabetic activity of glucagon [?]-like peptide-1. Duffy NA et al. Eur J Pharmacol. 2007 Jul 30;568(1-3):278-86.


Sulfonylurea Drugs and Prandin Cause Hypos when Combined with Some Other Drugs

The FDA has issued several updates to the prescribing information for Amaryl and other sulfs as well as for Prandin. They warn that their blood sugar lowering effect may be magnified when taken with other medications that slow their removal from the body. This may cause dangerous hypos.


The drugs that were already known to interact with Amaryl are: nonsteroidal anti-inflammatory drugs (Motrin, Advil, Ibuprofen); clarithromycin; and other drugs that are highly protein bound, such as salicylates (Aspirin, Salsalate), sulfonamides (Bactrim/Septra), chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and ß-adrenergic blocking agents.


Now the FDA warns that disopyramide (Norpace), fluoxetine (Prozac), and quinolones (Cipro, Noroxin, Levaquin etc) also potentiate the effects of sulfonylureas.


The warnings for Prandin now include gemfibrozil (Lopid) and immune suppressor cyclosporin.


My own experience has shown that the blood pressure amlodipine also seems to prolong the activity of repaglinide, and conversely that repaglinide strengthens the impact of the blood pressure pill.


If you are using Amaryl or another sufonylurea or Prandin, check with your pharmacist to make sure you aren't taking another drug that will cause these insulin-stimulating drugs to cause dangerous hypos. Doctors are woefully unaware of drug interactions and often prescribe drugs that should not be taken together. Details here FDA Safety Alerts (7/11/09)


Combining Prandin with metformin can also greatly amplify the impact of both drugs on blood sugar. The Prandin Prescribing Information reveals that over a 4-5 month period, people taking Prandin alone saw their blood fasting blood sugar rise by an average of 8 mg/dl, and people taking Metformin alone saw an average drop in their fasting blood sugar of 4.5 mg/dl, but people taking both drugs simultaneously experienced an average decline in fasting blood sugar of 39.2 mg/dl--almost ten times as much as with Metformin alone!


In addition, some people taking Prandin (including myself) have found that over time it can wear away the body's ability to raise blood sugars when they drop too low, resulting in the sudden onset of frighteningly low hypos. After 6 months of taking Prandin without incident I experienced two hypos in the 40 mg/dl range within one week, though I had not changed my diet or dose. I have heard similar stories from others. If this happens you must stop taking the drug as hypos in this range are very dangerous.


Do These Drugs Cause Beta Cell Burn-out?

There is some question about the wisdom of forcing exhausted and already dysfunctional beta cells to produce yet more insulin. Dr. Richard K. Bernstein is a firm believer that these kinds of drugs cause beta cells to burn out and die and counsels people with diabetes to avoid them. However, there is little experimental data available to evaluate this possibility.


Some argue that since the UKPDS data shows a similar decrease in blood sugar control in patients taking sulfonylurea drugs and Metformin, the sulfonylurea did not cause additional damage to beta cells.


A study published in 2008 shed some light on what might actually be happening with sulfonylurea-related beta cell burnout.:


Diabetes in Control: Mechanism for Sulfonylurea Treatment Failure in Type 2s Link to full research article: HERE.


If the suggested mechanism is in fact why beta cells burn out, burn-out might be avoided by cycling on and off these drugs.


Insulin Stimulating Drugs Are Associated with Weight Gain

Drugs that stimulate insulin production are known to cause weight gain. This may be because they cause the blood sugar fluctuations that we know make people hungry. Anecdotally many people report that these drugs do, in fact, make them very hungry.


Sulfonylureas Can Cause Hemolytic Anemia Especially in People with A Certain Genetic Condition


An FDA safety Alert published Auguest of 2009 reports:


Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Glynase PresTab belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.


Hemolytic anemia is a condition where the body stops making red blood cells. It can become an emergency. Symptoms of hemolytic anemia include Dark urine, Enlarged spleen, Fatigue, Paleness, Rapid heart rate, Shortness of breath, Yellow skin color (jaundice).


Because the G6PD deficiency is often only discovered when people react badly to a drug, it would be a good idea to get your blood count tested shortly after starting a sulfonylurea drug.


FDA Safety Alert for Glynase (micronized glyburide) tablets


Special Concerns about Diabetes Drugs in the Elderly

Here's a powerpoint presentation, prepared by pharmacist, that discusses some concerns that doctors should be aware of when prescribing diabetes drugs to the elderly. The definition of "elderly" used here is "65 and over."


Diabetes in Control: Diabetes Therapy in the Elderly Peter Pasik, David Joffe.


As we get older, our metabolisms slow down and a "normal" dose of a drug may have a stronger effect on our bodies since it doesn't get eliminated the way it would be in a younger person. According to this author, this can cause problems with low blood sugar in people who take drugs that stimulate the pancreas.

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