Back in the day, treating Type II Diabetes was very easy: We either gave patients the “blue pill” (Diabinese) or put them on Insulin. Today, we have a veritable smorgasbord of possibilities. Rather than prescribe a single agent, most practitioners favor a “cocktail” approach, using two, three, or even four different agents with a view to getting the HgbA1c down below 7.0%. But how does one choose? Here we have to have a good understanding of how these drugs work alone, and how they behave in concert.
Most practitioners start out with the old “veteran” drugs of metformin and sulfonylureas. The former decreases new glucose production from the liver, while increasing sensitivity to insulin. The latter drugs (glyburide, glipizide, glimepiride) push the pancreas to squeeze out more insulin. Alone or in combination, they can be quite effective… and they’re cheap. Unfortunately, they don’t always work. So what then?
Back in the 1990s, a new class of drugs was introduced called thiazoladinediones, or TZDs (Rezulin, Actos, Avandia). These acted by dramatically amplifying the action of insulin on its target cells, while reducing insulin resistance in muscle, fat and liver resulting in marked improvement in overall metabolism. However, liver toxicity from Rezulin and a lot of bad press concerning Avandia, caused these drugs to be pulled from the market. The lone survivor of this class has been Actos (pioglitazone), which has been dogged by undeserved negative publicity concerning possible bladder cancer. Actos does remain however, a very good tool for us to use (with certain limitations), and is very effective.
As we entered the new century, we have seen the rise of the “Incretin” agents: GLP-1 agonists and DPP-4 Inhibitors. GLP-1 is a naturally occurring protein secreted by the intestines when we eat. Its action results in decreased glucose output from the liver, increased release of insulin from the pancreas, slowed emptying from the stomach, and an increased sense of feeling full. These agents include Byetta, Bydureon and Victoza, which are administered by injection only… and they are somewhat expensive. However, they are potent agents that work very well alone or in combination with other drugs… and you can even lose some weight with them! DPP-4 Inhibitors (Januvia, Onglyza, Tradjenta, Nesina) slow down the breakdown of GLP-1 in the body, thus prolonging its effect. They are not as potent as the GLP-1 agonists, but are taken in pill form, thus avoiding the need for injection. They are also somewhat pricey. These drugs also come in fixed combinations with metformin, and in one case, with Actos as well.
The newest boys on the block are the SGLT-2 Inhibitors (Inkovana, Farxiga). These work by causing “dumping” of glucose in the urine, thus siphoning off sugar from the body. However, you have to have healthy kidneys for these agents to work. Being new, these are also relatively expensive. Used in combination with other drugs, they are quite effective, especially in those patients exhibiting some degree of insulin resistance, being able to circumvent insulin action altogether.
Now that we have a full “tool box”, how does your doctor decide what drugs to use? The American Association of Clinical Endocrinologists (AACE) has published a comprehensive management guide to help direct physicians in this endeavor. Obviously, therapy must be individualized to each patient, and thanks to our smorgasbord of drugs, there are a lot of choices. Most physicians begin with metformin, provided kidney function is adequate. This drug is cheap, effective, and does not generally cause hypoglycemia. If this does not bring the HgbA1c down, then a second drug is added. Which one depends on several factors, including kidney function, heart status, weight, and the doctor’s comfort level with the new medications. If two drugs prove inadequate, then a third drug may be added, or the patient may be started on insulin.
Today we have several new insulins available, all synthetically produced, which increase our therapeutic flexibility. Insulin regimens vary from single shot “basal” insulin administered at bed time (Lantus, Levemir) to multi-shot regimens of short acting insulin given before meals (Humalog, Novolog, Apidra), with or without a bedtime shot of long-acting insulin. We also have fixed combination insulins that are given twice a day at meal times (Humalog Mix 75/25, Novolog Mix 70/30). For convenience, the new insulin come in pre-filled pens which are easy to use, as well as traditional vials. Using caution, insulin may be combined with one or several oral agents, but makes the patient more prone to hypoglycemia.
Remember, the bottom line is to “get to goal”… i.e. attain an Hgb A1c of 7.0% or below (according to the American Diabetes Association), or 6.5% or below (according to AACE), be asymptomatic (no excessive thirst or urination), and prevent complications. Today, more than ever, we have the tools to get there.
Dr. William Shapse, MD
5341 W Atlantic Ave
Delray Beach, FL 33484