By: Robert Tanenberg
Physicians who treat people with type 2 diabetes face difficult choices when selecting the best medical therapy for each patient. The decision process is further complicated by the fact that because type 2 diabetes is a progressive disease, therapeutic agents that were initially successful may fail five or ten years later.
As recently as 1994, there were only two options for patients with type 2 diabetes: insulin and the sulfonylureas (such as glyburide and glipizide). The good news is that today, seven totally different classes of medications are available, as well as much better insulins. The bad news is that many physicians are more confused than ever, especially when faced with the option of combining two, three, or even more drugs at one time.
In addition, the past several years have seen the advent of six combination drugs (such as Glucovance, Avandamet, and Janumet), with more on the way. Faced with this explosion of therapeutic options, many physicians are reluctant to start insulin therapy even when it is clearly indicated.
Insulin Resistance and Deficiency in Type 2 Diabetes
Most patients with type 2 diabetes suffer from two major defects: insulin resistance and beta cell “burnout.” Insulin resistance typically precedes outright diabetes by several years, appearing in adults and children who are overweight, sedentary, and have a genetic predisposition to diabetes. Patients with insulin resistance are often diagnosed with the metabolic syndrome, which predisposes them to both type 2 diabetes and cardiovascular disease.
When food is ingested, insulin is secreted by the beta cells into the bloodstream. The insulin travels to the liver or muscles, where it attaches to receptors on the surface of the cells like a key in a lock. In non-diabetic people, this process allows individual glucose molecules to enter the cells of muscles, liver, and other organs. However, the cells of people with insulin resistance are “turned off” to the insulin key, so much of the glucose cannot enter the cells. The mother is calling, so to speak, but the children are not listening.
The pancreatic beta cells respond to this resistance by making extra insulin, which for a time keeps glucose in the normal range. If people with insulin resistance do not lose weight, exercise, and/or take certain medications, however, their beta cells may lose the ability to produce enough extra insulin to overcome their insulin resistance. That is the second defect in type 2 diabetes: a relative deficiency of insulin.
When the pancreatic beta cells can no longer overcome the insulin resistance, blood sugars begin to rise. Initially, only the post-meal glucose values are elevated, but in time the fasting glucose levels also increase. When fasting glucose tops 125 mg/dl, a patient is considered to have diabetes. It has been shown that when persons are first diagnosed with type 2 diabetes, they have already lost over fifty percent of their beta cell function.
Medications for Type 2 Diabetes
Fortunately, patients with type 2 diabetes often respond to dietary interventions, increased exercise, and weight loss. When more help is needed, oral diabetes medications such as metformin (Glucophage) or a thiazolidinedione drug (Actos or Avandia) can improve glucose levels by overcoming insulin resistance in the liver or muscle. Sulfonylurea drugs such as glipizide or Amaryl and their cousins (Starlix and Prandin) lower glucose levels by stimulating the remaining beta cells to make more insulin.
It is now known that people with type 2 diabetes are deficient in the intestinal hormones called incretins. Incretins are messenger molecules that travel to the pancreas to help beta cells make extra insulin during meals. The new drugs Byetta, Symlin, and Januvia are incretin substitutes. They not only raise insulin levels with meals, but also make that insulin more effective by slowing stomach emptying and reducing the harmful effects of glucagon (another pancreatic hormone that increases glucose).
Byetta and Symlin, both injected medicines, are unique because they produce satiety (a feeling of fullness) that often leads to significant weight loss. Januvia, an oral medication similar to Byetta in function, does not affect satiety or gastric emptying. Consequently, it does not help patients lose weight. On the other hand, it does not cause the nausea that commonly occurs in patients taking higher doses of Byetta.
In animals, these incretin – like drugs seem to prevent the destruction of the beta cells. Although there is no long-term evidence in humans that Byetta, Symlin, or Januvia preserve beta cells, we do know that, unlike the commonly used sulfonylureas, these newer drugs do not cause “burnout” of the beta cells.
(Refer to our Charts page for a complete list of type 2 medications).
When Medications Fail
Some patients can control their diabetes for years with a good diet and exercise routine plus one, two, or even three different medications. However, there are many conditions that may render these drugs either ineffective or no longer safe for the patient. These include:
- Acute infections or other serious illnesses
- Major surgery
- Congestive heart failure
- Kidney disease
- Liver disease
- Use of other drugs (prednisone and some psychiatric medications)
- Overeating or excessive weight gain
- Antibodies that destroy beta cells (in people with type 1, misdiagnosed as type 2)
- Progressive loss of beta cell function over many years
Unfortunately, many people with type 2 diabetes experience progressive loss of beta cell function. Their overworked beta cells seem to burn out, and drugs that were once effective can no longer hold their A1c’s below 7%. (For more information on A1c’s, see “What Is A1C And What Does It Measure?” and “Perfect Control“.)
The overwhelming majority of type 2s eventually require insulin to obtain or preserve satisfactory glucose control and an A1c of 7% or less. Research clearly shows that achieving good control early on prevents diabetic complications, including nerve, kidney, eye and heart disease, up to twenty years later.
Deciding exactly when to begin insulin therapy is problematic for physicians who treat type 2 diabetes. Patients’ misguided fears about needles, hypoglycemia, and weight gain often lead to reluctance and physician inertia. A recent survey found that fewer than half of all physicians made any change in diabetes therapy even for patients with A1c’s of over 9%.
A similar study at Johns Hopkins found that it took an average of 240 days before doctors added insulin or another drug for patients who could not achieve good control. By the time they finally took action, two-thirds of their patients had A1c levels approaching 10%.
Table 1 lists the relative and absolute indications for initiating insulin therapy in patients with diabetes. Even when initiation of insulin is clearly indicated, however, both patients and their physicians are often reluctant to do it. Some patients are needle-phobic, not realizing that modern insulin syringes and insulin pens are virtually painless.
Patients may also be worried about hypoglycemia and weight gain, although both of these concerns can be minimized. In cases where a doctor remains unwilling to start insulin for a patient whose glucose control is not improving even on two or three drugs, the patient should request consultation with an endocrinologist. Table 2 lists common concerns or barriers to initiation of insulin and some proven ways to overcome these obstacles.
In summary, most patients with type 2 diabetes will eventually need insulin to keep their diabetes in control. In general, the sooner insulin is started, the better off the patient will be in terms of preventing complications. Today’s modern insulins and treatment regimens (basal-bolus programs) make insulin a user-friendly therapy. Starting insulin early is the key to improved control and a longer and healthier life for all patients with type 2 diabetes.
Table 1: Indications for Starting Insulin
Table 2: How to Overcome Barriers to Starting Insulin
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