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Type 2 Diabetes Drugs
A Growing Number of Options

by Joshua J. Neumiller, PharmD, CDE, CGP, FASCP, and Sally To, PharmD

In recent years, the number of medicines approved to treat Type 2 diabetes has grown at an amazing rate. Metformin, which is often the diabetes drug of first choice today, came on the market in the United States in 1994. At that time, metformin, insulin, and a class of drugs known as sulfonylureas were the only medicines available to treat Type 2 diabetes. Today, in contrast, there are 11 classes of drugs on the market for Type 2 diabetes, with even more expected to appear in the not-too-distant future. While it is reassuring to have so many options available, trying to understand how all of these drugs work — and the pros and cons of each — can be a bit overwhelming. To help you get a handle on this, this article briefly reviews all drugs currently approved in the United States for the treatment of Type 2 diabetes.

Basics of Type 2 diabetes
Before delving into the topic of drugs and how they work to lower blood glucose, it helps to understand what happens in Type 2 diabetes that leads to elevated blood glucose levels.

While ongoing research is always expanding our knowledge of what happens in Type 2 diabetes, the condition is known to stem from three related but distinct problems: insulin resistance, reduced insulin production, and overproduction of glucose by the liver.

The pancreases of people with Type 2 diabetes often produce insulin just fine, but a hallmark of the condition is that their bodies cannot use the hormone efficiently. This resistance to the effects of insulin, aptly known as insulin resistance, makes it more difficult for the body’s cells to “take up” glucose from the bloodstream and use it for energy — since insulin controls this process.

When a person is insulin resistant, the pancreas is forced to produce more insulin to maintain normal blood glucose levels. Over time, this stresses the pancreas until it cannot keep up with the insulin needs of the body. Eventually the pancreas may become “burned out” and lose its ability to make insulin altogether.

Finally, in people with Type 2 diabetes the liver tends to produce excess glucose, raising the blood glucose level inappropriately. Normally, the liver releases just enough glucose into the bloodstream to keep the body running smoothly. In the presence of insulin resistance, however, the signals telling the liver to stop releasing glucose don’t work, and it continues to release it even when blood glucose levels are too high.

Together, these three processes (and others that we are still learning about) lead to hyperglycemia, or high blood glucose.

ADA/EASD algorithm
While this article covers all drugs and therapies currently available to treat Type 2 diabetes, it is important to note that expert medical bodies recommend using some of these drugs before using others. The American Diabetes Association (ADA), along with the European Association for the Study of Diabetes (EASD), released the latest version of an algorithm in 2009 that recommends an order of treatment for Type 2 diabetes. An algorithm is a set of steps to follow to achieve a desired end; in this case, the desired end is a diabetes regimen that keeps blood glucose levels in target range.

Many health-care providers use this algorithm to guide their treatment decisions for people with Type 2 diabetes, starting with metformin and lifestyle changes at diagnosis and proceeding to other recommended therapies as needed. The algorithm groups treatments into Tier 1, “well-validated therapies”, and Tier 2, “less well-validated therapies.”

Tier 1 includes metformin, the sulfonylurea class of drugs, long-acting (basal) insulin, and intensive insulin therapy, (using both long- and short-acting insulin). Tier 2 includes the drug classes of thiazolidinediones and GLP-1 receptor agonists. Other drugs that are not included in the algorithm but may benefit certain individuals include DPP-4 inhibitors, meglitinides, alpha-glucosidase inhibitors, colesevelam, and bromocriptine.

Metformin
Metformin (brand name Glucophage and others) is considered to be the first-line drug for treating Type 2 diabetes. It works in several ways, the most important of which is limiting the release of glucose from the liver. Metformin also reduces insulin resistance, allowing the body to use insulin more efficiently. Some other benefits of metformin are that it carries a low risk of hypoglycemia (low blood glucose) and doesn’t tend to cause weight gain, a common side effect of many other diabetes drugs.

Because metformin is removed from the body by the kidneys, it should be used with caution by people with impaired kidney function. The most common side effects of metformin are nausea, diarrhea, gas, and abdominal pain. These side effects can be minimized by taking the drug with meals and by slowly increasing the dose from a low starting level. Metformin comes in many different doses and pill types; it is also available in liquid form for people who have trouble swallowing pills. Metformin can also be taken as part of a combination pill with a number of other drugs, allowing people who require both drugs to take fewer pills each day. Metformin has been shown to lower HbA1c — a measure of long-term blood glucose control — by 1% to 2%. The HbA1c level of people without diabetes tends to be between 4% and 6%, and the target level for most people with diabetes is 7%.

Sulfonylureas
Sulfonylureas are a class of drugs often prescribed to people who are taking metformin but need a little more help to lower their blood glucose. The three most commonly used sulfonylureas are glimepiride (brand name Amaryl), glipizide (Glucotrol), and glyburide (Diabeta, Micronase). These drugs are known as “insulin secretagogues,” which means that they stimulate the pancreas to produce more insulin. They are generally taken by mouth once or twice daily.

Because sulfonylureas work by increasing insulin levels in the body, their most common side effects are hypoglycemia and weight gain. Sulfonylureas can lower HbA1c by 1% to 2%.

Basal insulin
Insulin is the hormone that allows cells throughout the body to use glucose in the blood for energy. Because people with Type 2 diabetes have insulin resistance, insulin injections are often used to overcome this resistance by increasing the amount of insulin in the body. There are two broad categories of injected insulin: basal insulin, which provides a steady level of insulin throughout the day; and mealtime insulin, which is used to “cover” the expected rise in blood glucose following a meal (the mealtime dose is often called a bolus of insulin). Basal insulin can be a simple and effective treatment for Type 2 diabetes. The ADA recommends adding basal insulin to metformin for people who are not meeting their blood glucose goals on metformin alone, or on metformin plus a sulfonylurea.

There are three varieties of basal insulin currently available: NPH insulin (Humulin N, Novolin N), insulin glargine (Lantus), and insulin detemir (Levemir). NPH is usually taken two or three times daily. It typically works in the body for 10–12 hours and has a “peak” of intensified action about 4–6 hours after it is injected. Because of this peak, injections of NPH must be timed carefully with respect to meals and exercise to avoid hypoglycemia.

Insulin glargine (Lantus) and insulin detemir (Levemir) are usually taken once daily, although some people do require two injections per day. They stay at a near-constant level within the blood circulation for approximately 24 hours and have little if any peak. Consequently, glargine and detemir can pose a lower risk of hypoglycemia than NPH. However, NPH is considerably cheaper than glargine or detemir.

Common side effects of insulin include injection site discomfort, hypoglycemia, and weight gain. With proper use, however, these risks can be minimized or even avoided entirely.

Intensive insulin therapy
Intensive insulin therapy refers to the use of basal and mealtime insulins together. Regular insulin (Humulin R, Novolin R) has been on the market longer than any other mealtime insulin currently available. Regular insulin is usually taken before each meal, 30–45 minutes prior to eating. Many people are quite satisfied with Regular insulin, but others find that remembering to take an injection 30–45 minutes before a meal can be difficult, or that it is hard to time injections correctly to avoid either a blood glucose spike or hypoglycemia. For these people, a “rapid-acting” insulin may be best; these insulins can be taken about 15 minutes before, or even immediately prior to, eating. Rapid-acting insulins currently on the market include insulin aspart (NovoLog), insulin lispro (Humalog), and insulin glulisine (Apidra). While more convenient, these insulins are considerably more expensive than Regular insulin.

Most insulin products sold today come in a variety of forms, including vials, prefilled insulin pens, and prefilled cartridges for use in insulin pens. Premixed insulin products containing both a basal and a shorter-acting insulin are also available.

Compared with other drugs used to treat Type 2 diabetes, insulin has the greatest ability to lower blood glucose and HbA1c — unlike most drugs, doses of insulin can usually be increased (or decreased) to whatever level is needed to achieve desired results. This should only be done, of course, under the guidance of a qualified health-care provider.

Thiazolidinediones
Often referred to as the “glitazones,” thiazolidinediones include both pioglitazone (Actos) and rosiglitazone (Avandia). These drugs are taken by mouth and work by reducing insulin resistance. Pioglitazone is considered to be a Tier 2, or less well-validated, therapy for Type 2 diabetes. Because of concerns that rosiglitazone may increase the risk of heart attack, its use is restricted in the United States. Pioglitazone, on the other hand, does not have any special restrictions on its use.

Thiazolidinediones can lower HbA1c by 1% to 2% but may take up to 12 weeks to reach their full blood-glucose-lowering potential. Common side effects of these drugs include weight gain and fluid retention. Because the risk of fluid retention is already high in people with heart failure, thiazolidinediones should not be taken by this population.

GLP-1 receptor agonists
This class of drugs is relatively new, with its first member, exenatide (Byetta), becoming available in the United States in 2005. The other drug in this class is liraglutide (Victoza), which was approved in 2010. Both drugs work by mimicking the actions of a natural hormone produced in the body called glucagon-like peptide-1 (GLP-1). They help lower blood glucose by telling the pancreas to produce more insulin following a meal and by decreasing production of another hormone — glucagons — that signals the liver to release glucose.

Exenatide is taken by injection twice daily and is approved for use alone or in combination with a variety of oral diabetes drugs. Liraglutide is also taken by injection, but only once daily. Both products are sold in prefilled pens (similar to insulin pens). These drugs can lower HbA1c by about 1%.

Another big advantage of these drugs is that their use often leads to weight loss. This occurs because they slow the rate at which food is moved from the stomach to the intestines, thus prolonging the feeling of fullness after a meal. They may also signal the brain to directly reduce feelings of hunger. Common side effects of these drugs include nausea and vomiting, particularly when just starting therapy. It is important with either drug to increase the dose slowly from a low level to avoid these side effects as much as possible. Exenatide is removed from the body by the kidneys and is therefore not recommended for people with impaired kidney function. This is not the case for liraglutide, however, so people with kidney problems can usually take liraglutide if they are unable to take exenatide for this reason.

DPP-4 inhibitors
Dipeptidyl-peptidase-4 (DPP-4) inhibitors are not included in the ADA/EASD algorithm as a recommended treatment for Type 2 diabetes — in fact, none of the remaining treatments discussed in this article are. But like other classes of drugs that will follow, DPP-4 inhibitors are approved to treat Type 2 diabetes and may be helpful to some individuals. DPP-4 inhibitors work in a way similar to that of GLP-1 receptor agonists. But while those drugs mimic the naturally occurring hormone GLP-1, DPP-4 inhibitors block the action of an enzyme (known as DPP-4) that breaks down GLP-1 throughout the body. By slowing the effects of this enzyme, DPP-4 inhibitors allow GLP-1 to stay in the body longer (where the hormone increases insulin production and reduces the release of glucose from the liver).

There are currently three DPP-4 inhibitors approved for use in the United States: sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Tradjenta). Advantages of DPP-4 inhibitors include once-daily oral dosing and a low risk of hypoglycemia. Common side effects of DPP-4 inhibitors include headache, upper respiratory tract infection, and sinus infection.

Meglitinides
Nateglinide (Starlix) and repaglinide (Prandin) are the two currently available drugs that belong to the meglitinide family. This class of drugs works in a way very similar to that of sulfonylureas, leading to increased insulin production in the pancreas. However, meglitinides are short-acting, taking effect within 15–30 minutes of being ingested and lasting for only 4–6 hours. They should be taken within 30 minutes of beginning a meal and are usually taken three times per day — but should be skipped if a meal is skipped.

Because meglitinides work by increasing the amount of insulin in the body, common side effects include hypoglycemia and weight gain. Taking them as directed with meals, however, lowers the risk of hypoglycemia. Although nateglinide is available as a generic, meglitinides tend to be more expensive than sulfonylureas.

Pramlintide
Pramlintide (Symlin) is an injectable drug that is sometimes taken alongside mealtime insulin. It is a synthetic version of amylin, a hormone that is normally released from the pancreas along with insulin and may be lacking in people with Type 2 diabetes. Pramlintide works with insulin to regulate blood glucose levels after meals, effectively increasing the potency of insulin. It is taken by injection immediately before a meal and should never be mixed with insulin or any other drug in the same syringe. Potential benefits of pramlintide include allowing users to take less insulin with each meal, which may in turn lead to some weight loss. A major concern with the drug, however, is the risk of severe hypoglycemia it carries — particularly for people just starting to take it. People who begin to take pramlintide must reduce their mealtime insulin dose by about half, or as instructed by their doctor, to avoid a potentially dangerous drop in blood glucose. While weight loss and improved blood glucose control are not benefits to scoff at, the risk of hypoglycemia and the need for three or more additional injections per day are drawbacks of pramlintide. It is also only available as a brand-name medicine and can therefore be expensive under many insurance plans.

Alpha-glucosidase inhibitors
Digestive enzymes in the small intestine break down complex carbohydrates (found in grains, fruits, and vegetables) into simple sugars — such as glucose — that can be absorbed and used for energy. Alpha-glucosidase inhibitors, namely acarbose (Precose) and miglitol (Glyset), are drugs that block the enzyme alpha-glucosidase and thus slow the breakdown of complex carbohydrates. This delays the absorption of glucose from the digestive tract, resulting in less of a rise in blood glucose level following a meal. To be effective, these drugs should be taken with the first bite of a meal. Because of the way they work, alpha-glucosidase inhibitors commonly cause abdominal pain, bloating, gas, and diarrhea. These drugs can lower HbA1c by about 0.5%, a benefit often deemed too small to justify the unpleasant side effects they tend to cause. However, if the dose of these drugs is increased slowly from a low level, they can be well tolerated by some people.

Colesevelam
Colesevelam (Welchol) is a cholesterol-lowering drug that was recently approved to help lower blood glucose in people with Type 2 diabetes. It can lower HbA1c by about 0.5% and also lowers LDL (low-density lipoprotein, or “bad”) cholesterol. This drug is believed to work by reducing the absorption of carbohydrates by the digestive system. Colesevelam is taken once or twice daily with meals; common side effects include constipation, indigestion, and nausea. While colesevelam can lower LDL cholesterol, it may increase the blood triglyceride level, so this drug is generally not a good fit for people with very high triglycerides. A major concern with colesevelam is that it can interact with several other drugs. It is therefore very important to let your health-care providers know about all drugs you take prior to starting colesevelam.

Bromocriptine
Bromocriptine (Cycloset) was used to treat neurological conditions such as Parkinson disease before being approved to treat Type 2 diabetes in 2009. Studies of this drug have shown that it leads to improved blood glucose control as well as some weight loss. While the exact mechanism of its action is unknown, it is believed that bromocriptine helps regulate the circadian rhythm (the normal cycle of hormones and other physiological processes throughout the day) of people with Type 2 diabetes. Cycloset is normally taken with food within two hours of waking up. Common side effects include hypotension (low blood pressure), fainting, nausea, vomiting, diarrhea, and constipation.

What’s right for you
There are more options for treating Type 2 diabetes than most people could have imagined 20 or even 10 years ago. And while the American Diabetes Association recommends only certain treatments and the order in which they should be prescribed, its guidelines also recognize that people with diabetes have individual needs to which therapies should be tailored. The course of treatment should take not just blood glucose, but also factors such as body weight, risk of hypoglycemia, and the cost of drugs into account. Whether you’ve been recently diagnosed or have had diabetes for years, talk to your doctor, pharmacist, or diabetes educator if you have any questions or doubts about your current treatment. If your blood glucose control is not where you want it or you’re troubled by side effects, there may be something else on the menu of options that’s right for you.

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