What’s New in the Treatment of Diabetes?
By Sarfraz Zaidi, MD

The treatment of diabetes has gone through revolutionary changes. Most Type 2 diabetics can now avoid ending up on insulin injections. Most do very well with new oral medications.
“Mark” came to see me for his diabetes, after suffering three angioplasties in two years. Mark, like 95% of diabetics, had Type 2 diabetes. Despite following his doctor’s advice and following his anti-diabetic regimen, including diet, exercise and insulin injections, he developed severe coronary artery disease. He was quite demoralized. Heart disease is the number one killer of diabetics.

Compared to non-diabetics, patients with diabetes have a six fold increased risk for a heart attack. The reason for this increased risk is a phenomenon called Insulin Resistance, the root cause for Type 2 diabetes, as well as heart attacks and strokes.
Therefore, now we treat diabetes by treating insulin resistance.What is insulin resistance and how does it cause heart attacks and strokes? Insulin is a chemical produced by the pancreas in our body. One of the main functions of insulin is to drive glucose from the blood into the cells, especially muscle cells, where it is used as a fuel to produce energy.

Think of insulin as the doorman who opens the door for glucose to get into the cell. In individuals prone to Type 2 diabetes, the hinges on the door of the cell are rusty. Consequently, insulin cannot easily open the doors. Now instead of one doorman, you need three or four doorman to pry the door open. This is called insulin resistance. In response to insulin resistance, the pancreas produces more and more insulin, which keeps blood sugar normal for some time. If insulin resistance is not treated, the pancreas eventually becomes exhausted and insulin production starts to drop.

This causes blood sugar to start rising and eventually, a person becomes diabetic.
It takes about one to two decades of insulin resistance before a person becomes diabetic. During this time, insulin resistance causes many other changes in our body which are quite harmful. For example, insulin resistance increases serum triglycerides (the fat in the blood), lowers HDL cholesterol (the good cholesterol) and changes LDL cholesterol (the bad cholesterol) from type A (less dangerous) to Type B (more dangerous). Insulin also increases blood pressure in these patients. In addition, Insulin resistance makes it easier for blood to clot and impairs our body’s natural ability to break down any clots.

All of these abnormalities set the stage for a heart attack and stroke.Why is the old fashioned treatment of diabetes flawed?When I first saw Mark, his diabetes was out of control, because his diabetes was being managed by an old fashioned, outdated treatment plan. For years, he was taking Glyburide, which initially controlled his diabetes. However, after a few years, he had to go on insulin shots to control his blood sugar. Glyburide is an old drug and belongs to the class of drugs known as sulfonylurea drugs. (Other drugs in this class include Glipizide, Glimepiride and Chlorpropamide. In the US, these drugs are available under the brand names of Diabeta, Micronase and Glynase for glyburide, Glucotrol for glipizide, Amaryl for glimepiride and Diabenes for chlorpropamide).

Before 1994, these were the only oral drugs available in the US for the treatment of Type 2 diabetes. These sulfonylurea drugs act by stimulating the pancreas to produce more insulin, but do not treat insulin resistance. It’s like flocking a tired horse to keep going. Eventually it slows down, stumbles and drops dead.

“Mark’s” exhausted pancreas, like a tired horse, could not produce enough insulin despite stimulation from sulfonylurea drugs. Eventually, he was placed on insulin shots to control his diabetes. However, once again, it was a poor strategy for controlling his diabetes. The reason? Sulfonylurea drugs and insulin shots do not treat insulin resistance. Consequently, most diabetic patients, including Mark, develop coronary heart disease requiring angioplasties or even heart bypass surgery. They are also at high risk for stroke. The new treatment of diabetesDoctors involved in research for treatment of diabetes eventually realized that to effectively treat Type 2 diabetics, insulin resistance must be treated. The treatment for diabetes started to change in 1994 with the release of Glucophage (metformin), which treats insulin resistance at the level of the liver.

However, in a diabetic, insulin resistance develops at three levels: muscle, fat and the liver. Therefore, metformin alone is not enough to adequately treat
insulin resistance.

In 1997, Rezulin (troglitazone) and then in 1999, Actos (pioglitazone) and Avandia (rosiglitazone) were released. These drugs treat insulin resistance at the level of muscle and fat. Rezulin was later taken off the US market because of its association with some cases of liver toxicity. However, Actos and Avandia have proven to be safe and do not cause liver toxicity.

By combining metformin (Glucophage) with Actos or Avandia, we can effectively treat insulin resistance at all three levels. Besides controlling blood glucose, Actos and Avandia also reduce triglycerides, increase HDL cholesterol and re-establish the body’s ability to break clots and therefore, reduce the risk for heart attack and stroke.

Diabetics who undergo balloon angioplasty of narrowed coronary arteries frequently develop another blockage after just a few months. This occurs due to the formation of a new layer of lining in the coronary blood vessel wall, known as neo-intima. Actos and Avandia reduce neo-intima formation and therefore, have the potential to decrease the need for repeated angioplasties. In a recently published study, Avandia was shown to significantly reduce the need for repeated coronary angioplasties.

In another study, Actos was shown to reduce narrowing of carotid arteries in the neck. This is a significant finding, as people with narrowed carotid arteries are at a high risk for stroke. By reducing insulin resistance, Actos and Avandia reduce the burden of excessive insulin production by the pancreas. Relieved of the stress of overproduction of insulin, the pancreas begins to work efficiently once again. As a result, these patients usually do not have to resort to insulin injections.

This certainly has been our experience at the Jamila Diabetes and Endocrine Medical Center. By using these new drugs, we have been able to take most of our
patients off insulin injections. Mark was one of those patients. With the new combination therapy of treating insulin resistance with Glucophage and Actos, his diabetes came under much better control. We gradually took him off his insulin injections. Naturally, he was quite thrilled that he no longer had to endure insulin injections. More impressively, he hasn’t had any more coronary angioplasties in the last seven years. There is another new class of drugs that specifically target blood glucose rise after meals. These drugs are Repaglinide (Prandin) and Nateglinide (Starlix). These drugs work by increasing insulin production for a short period of time (about four to six hours, as compared to twelve to twenty-four hours of sulfonylurea drugs.) Therefore these drugs are used to control the rise of blood glucose after meals. These drugs are taken at the start of a meal.

Another class of anti-diabetic drugs includes Acarbose (Precose) and Miglitol (Glyset). These drugs act by preventing some glucose absorption from the intestines. By themselves, they are weak drugs and need to be combined with other drugs.Every drug has some potential sideeffects Sulfonylurea drugs can cause episodes of low blood sugar, which causes terrifying symptoms such as shakiness, heart pounding, perspiration and fuzzy thinking. If you aren’t treated promptly, you can lapse into a coma. On the other hand, Pioglitazone (Actos), Rosiglitazone (Avandia) and Metformin (Glucophage) do not cause low blood sugar. Sulfonylurea drugs usually cause some weight gain as well.

A major disadvantage of sulfonylurea drugs is that they eventually lead to pancreas exhaustion and then patients have to go on insulin injections. Repaglinide, nateglinide, acarbose and miglitol can also cause low blood sugar.
Actos and Avandia can cause weight gain and congestive heart failure in some patients.

Metformin can cause some stomach upset as well as diarrhea. Occasionally, it causes a metallic taste in the mouth and Vitamin B12 deficiency. Rarely, Metformin can cause a serious side-effect known as Lactic acidosis, which can be life-threatening. This rare sideeffect develops if metformin is used in patients with kidney failure, liver disease or other serious diseases such as pneumonia.

Procedures that require contrast agents, such as CT scans and angiograms, can occasionally induce kidney failure in diabetic patients. Therefore, patients should not take Metformin for up to 48 hours after such a procedure. Then a blood test should be done to check kidney function before restarting metformin. Diet and exercise are extremely important
Diet is an extremely important and often misunderstood part of diabetic treatment. Patients with Type 2 diabetes on oral medications need to eat only three small meals a day. No snacks. Reduce the amount of bread, pasta and rice. Avoid cereals, donuts, muffins, croissants and other bakery products. Say no to desserts and pizza. Don’t drink sodas or juices as they are loaded with sugar. Fruits are good and bad for us. They provide us with vitamins, but are loaded with natural sugar. Therefore, eat no more than one
fresh fruit a day. Take a daily multivitamin to keep your vitamins optimized.

Daily exercise is crucial to the proper management of diabetes. Aerobic exercise for about 30 minutes a day reduces insulin resistance and blood sugar starts decreasing. Start exercise slowly by walking for about 10 minutes. Gradually increase to brisk walking for about 30 minutes a day. Before embarking on any exercise plan, discuss it with your physician.

In summary, every Type 2 diabetic patient, in addition to diet and exercise, should be on metformin (Glucophage) and pioglitazone (Actos) or rosiglitazone (Avandia), provided there are no contra-indications to the use of these drugs. If diabetes is still uncontrolled, then another anti-diabetic drug, such as Prandin, Starlix or glyburide, can be added. With this new approach, we not only control blood glucose, but also reduce the devastating complications of diabetes, especially heart disease and stroke.


Editor: Akhtar M. Faruqui
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