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Combination Therapy for Diabetes

11 July 2011
Many people with type 2 diabetes can manage blood sugar levels effectively on oral
diabetes medications and lifestyle changes alone. Others will need to combine oral
diabetes medications with injectable diabetes drugs in order to bring their blood glucose
levels into a healthy range. Finding the right combination is the key to managing diabetes
For years, insulin was the only injectable diabetes medication available to help control
blood sugar. Today, several newly approved injectable diabetes drugs are available. A
growing number of medication options are also available, so doctors can individualize
diabetes treatment with greater precision than ever before.
Combining Diabetes Medications for Optimal Effect
How will your doctor decide the best diabetes drug regimen for you? The first principle
is to make life as easy and therapy as effective as possible, says Daniel Einhorn, MD,
president of the American Association of Clinical Endocrinologists and medical director
of the Scripps Whittier Diabetes Institute in La Jolla, Calif. Type 2 diabetes is a lifelong
problem. We want to choose therapies that people can easily live with.
One factor is how comfortable people feel giving themselves injections. Some patients
are fine with injectable medications. Others will do anything not to have to give
themselves injections, says Eleftheria Maratos-Flier, MD, professor of medicine at Beth
Israel Deaconess Medical Center in Boston.
The second principle of combination diabetes drug therapy, according to Einhorn, is
choosing medication therapies that work in complementary ways. Today we have a
variety of drugs that work in very different ways, so combinations can be especially
effective, says Einhorn.
One of the most commonly used oral drugs, metformin (sold under the brand names
Blumetza, Fortamet, Glucophage, and Riomet), is considered the cornerstone of most
combination therapy. It works by decreasing the amount of glucose produced by the liver.
Metformin can be paired with insulin or with a GLP-1 agonist, which stimulates insulin
Doctors may also combine insulin with a GLP-1 agonist and a thiazolidinedione oral
medication (Actos and Avandia), which sensitizes the body to insulin. For people
comfortable with using injectable drugs, doctors may recommend one of the two new
GLP-1 agonists, Byetta and Victoza. For people who dont want an injectable drug, the
alternative is a DPP-4 inhibitor (Januvia, Tradjenta, and Onglyza), which is taken orally.
Both of these classes of drugs work in a similar way and are considered equivalent.

Weighing the Pros and Cons of Drug Combinations

Minimizing adverse effects is also important. Some diabetes medications can cause blood
sugar levels to drop too low, causing hypoglycemia. The oral medication sulfonylurea
(DiaBeta, Glynase, Micronase), which has long been used for type 2 diabetes, poses a
moderate risk of causing hypoglycemia. Many doctors prefer to prescribe metformin,
which is much less likely to cause hypoglycemia. Metformin is often paired with a GLP1 agonist because these new injectable drugs work only when blood sugar levels are high,
further avoiding hypoglycemia.
Body weight is another issue doctors consider in choosing a combination diabetes
therapy. Many people with type 2 diabetes are overweight or obese. Excess body weight
worsens blood sugar control. Unfortunately, some oral agents, such as Actos and Avandia,
tend to cause weight gain. Insulin also tends to promote weight gain.
Since being weight increases diabetes risk and poses other health problems, we want to
try to choose medications that help people maintain a healthy weight whenever possible,
says Einhorn. The first choice for oral diabetes medication is typically metformin, which
does not promote weight gain. In overweight or obese patients, it is often paired with a
GLP-1 agonist. These new agents have been shown to suppress appetite and increase
satiety, helping roughly 30% of patients on them to lose modest amounts of weight.
Almost all drugs have unwanted side effects in some people, of course. Metformin can
cause nausea, abdominal pain, and diarrhea in a very small percentage of patients. GLP-1
agonists can also cause gastrointestinal side effects. We do have a small percentage of
patients who go off them because they just cant tolerate the side effects, says Marina
Basina, MD, clinical assistant professor of medicine in the division of endocrinology at
Stanford University in Stanford, Calif. But most patients do well on them.
Patients who cant tolerate GLP-1 agonists may fare better on another new injectable
diabetes drug, called pramlintide (Symlin). A synthetic form of a naturally occurring
hormone that helps the body maintain normal blood sugar levels, pramlintide is approved
for use when insulin alone does not adequately lower blood glucose levels.
A Matter of Trial and Error
Choosing the best diabetes therapies is as much an art as a science. The American
Diabetes Association publishes annual treatment guidelines. Leading professional groups
also release recommendations. But the field of diabetes treatment is changing so fast that
some guidelines may be out-of-date almost as soon as theyre published, says MaratosFlier. The only way to find the best therapeutic regimen is through trial and error.
Theres almost no way to know in advance how patients will respond to a given
medication or combination of medications.
Whats more, drug regimens must be tailored to the individual patient. There is no single
best combination for all patients, says Basina. And over time, we often have to change

the regimen if patients stop responding to a certain drug or develop side effects.
To make sure your diabetes medication regimen is working adequately, its important to
monitor blood sugar levels. How often you test blood sugar levels will depend on the
medications youre taking and how well your blood sugar levels are controlled.
The sooner you bring blood sugar levels down to normal, and the better control you
have over time, the less likely your diabetes is to progress, says Einhorn.