Many types of anti-hyperglycemic drugs are available to help patients with type 2 diabetes control their blood sugar levels. Most of these drugs are aimed at using or increasing sensitivity to the patient's own natural stores of insulin.
Older oral hypoglycemic drugs -- particularly metformin -- are less expensive and generally work as well as newer diabetes drugs. Metformin is usually recommended as the first-line drug.
Adding a second oral hypoglycemic drug may be recommended if adequate control is not achieved with the first medication. For the most part, doctors should add a second drug rather than trying to push the first drug dosage to the highest levels.
Metformin (Glucophage, generic) is a biguanide, which works by reducing glucose production in the liver and by making tissues more sensitive to insulin. Doctors recommend it as a first choice for most patients with type 2 diabetes. Metformin may also be used in combination with other drugs.
Metformin does not cause hypoglycemia or add weight, so it is particularly well-suited for obese patients with type 2 diabetes. Metformin also appears to have beneficial effects on cholesterol and lipid levels and may help protect the heart. It is also the first choice for children who need oral drugs.
Side Effects. Side effects include:
- A metallic taste
- Gastrointestinal problems, including nausea, and diarrhea
- Interference with absorption of vitamin B12 and folic acid
- Rare reports of lactic acidosis, a potentially life-threatening condition, particularly in people with risk factors for it. Major studies, however, found no greater risk with metformin than with any of the other drugs used for type 2 diabetes.
Certain people should not use this drug, including anyone with heart failure or kidney or liver disease. It is rarely suitable for adults over age 80.
Sulfonylureas are oral drugs that stimulate the pancreas to release insulin. A number of brands are available including chlorpropamide (Diabinese, generic), tolazamide (Tolinase, generic), glipizide (Glucotrol, generic), tolbutamide (Orinase, generic), glyburide (Micronase, generic), and glimepiride (Amaryl, generic). For adequate control of blood glucose levels, the drugs should be taken 20 - 30 minutes before a meal.
Most patients can take sulfonylureas for 7 - 10 years before they lose effectiveness. Combinations with small amounts of insulin or other oral anti-hyperglycemic drugs (such as metformin or a thiazolidinedione) may extend their benefits. A combination of glyburide and metformin in one pill (Glucovance) is available.
Side Effects and Complications. In general, women who are pregnant or nursing or by individuals who are allergic to sulfa drugs should not use sulfonylureas. Side effects may include:
- Weight gain (some sulfonylureas, such as glimepiride, may produce less weight gain than others)
- Water retention
- Although sulfonylureas pose a lower risk for hypoglycemia than insulin does, the hypoglycemia produced by sulfonylureas may be especially prolonged and dangerous. The newer sulfonylureas, such as glimipiride, have much less risk of hypoglycemia than older sulfonylureas.
- Some sulfonylureas may pose a slight risk for cardiac events.
Sulfonylureas interact with many other drugs, and patients must inform their doctor of any medications they are taking, including over-the-counter drugs or herbal supplements.
Meglitinides stimulate beta cells to produce insulin. They include repaglinide (Prandin) and nateglinide (Starlix, generic). These drugs are rapidly metabolized and short-acting. If taken before every meal, they mimic the normal effects of insulin after eating. Patients, then, can vary their meal times with this drug. These drugs often used in combination with metformin or other drugs.
Side Effects. Side effects include diarrhea and headache. As with the sulfonylureas, repaglinide poses a slightly increased risk for cardiac events. (Newer drugs, such as nateglinide, may pose less of a risk.) People with heart failure or liver disease should use them with caution and be monitored.
Thiazolidinediones, also known as peroxisome proliferator-activated receptor (PPAR) agonists, include pioglitazone (Actos, generic) and rosiglitazone (Avandia). Thiazolidinediones are taken as pills, usually in combination with other oral drugs or insulin. Thiazolidinediones available as 2-in-1 pills include rosiglitazone and metformin (Avandamet), rosiglitazone and glimepiride (Avandaryl), pioglitazone and metformin (Actoplus Met), and pioglitazone and glimepiride (Duetact).
Side Effects. Thiazolidinediones can have serious side effects. They can increase fluid build-up, which can cause or worsen heart failure in some patients. Combinations with insulin increase the risk. Patients with heart failure should not use them. People with risk factors for heart failure should use these drugs with caution.
In particular, rosiglitazone has been associated with increased risks for heart attack and heart failure. The FDA advises that due to its cardiovascular risks, rosiglitazone should only be used by patients who are already taking the drug or patients whose blood sugar is not well controlled by other diabetes medications and who do not wish to take pioglitazone. Patients who take rosiglitazone, especially those who have heart failure, heart disease, or who are at high risk for heart attack, should talk to their doctor about their treatment options.
Thiazolidinediones may cause more weight gain than other diabetes medications or insulin. Any patient who has sudden weight gain, water retention, or shortness of breath should immediately call their doctor. These drugs have also been linked to increased risks for bone fracture. The FDA is currently investigating whether pioglitazone may increase the risk for bladder cancer.
There have been rare reports of rosiglitazone causing or worsening diabetic macular edema. This is an eye condition associated with diabetic retinopathy that causes swelling in the macular area of the retina. Symptoms include blurred vision and decreased color sensitivity. Most patients who had this side effect also had swelling in the feet and legs (peripheral edema). The condition resolved or improved when patients stopped taking the drug.
Thiazolidinediones can also cause liver damage. Patients who take these drugs should have their liver enzymes checked regularly.
Alpha-glucosidase inhibitors, including acarbose (Precose, generic) and miglitol (Glyset), reduce glucose levels by interfering with the absorption of starch in the small intestine. Acarbose tends to lower insulin levels after meals, a particular advantage, since higher levels of insulin after meals are associated with an increased risk for heart disease.
Side Effects. These medications need to be taken with meals. Unfortunately, about a third of patients stop taking the drug because of flatulence and diarrhea, particularly after high-carbohydrate meals. The drug may also interfere with iron absorption.
Alpha-glucosidase inhibitors do not cause hypoglycemia when used alone, but combinations with other drugs do. In such cases, it is important that the patient receive a solution that contains glucose or lactose, not table sugar. This is because acarbose inhibits the breakdown of complex sugar and starches, which includes table sugar.
GLP-1 Inhibitors (Exenatide and Liraglutide)
Incretin mimetics belong to a new class of drugs that help improve blood sugar control. Incretins include glucagon-like peptide-1 (GLP-1) inhibitors and DDP-4 inhibitors. GLP-1 inhibitors are given by injection and are prescribed for patients with type 2 diabetes who have not been able to control their glucose with metformin or a sulfonylurea drug. They can be taken in combination with these drugs or alone.
Exenatide (Byetta) was the first GLP-1 inhibitor drug. It is a synthetic version of the hormone found in the saliva of the Gila monster, a venomous desert lizard. Exenatide is injected twice a day, 1 hour before morning and evening meals. Bydureon is an extended-release version of Byetta that requires injection only once a week. Liraglutide (Victoza) is another GLP-1 inhibitor that is injected once a day.
Side Effects. These drugs stimulate insulin secretion only when blood sugar levels are high and so have less risk for causing low blood sugar (hypoglycemia) when they are taken alone. However, the risk for hypoglycemia increases when GLP-1 inhibitors are taken along with a sulfonylurea drug. There does not appear to be a risk for hypoglycemia when they are used along with metformin. Other side effects may include nausea, vomiting, and diarrhea.
Exenatide and liraglutide have been associated with cases of acute pancreatitis, which is sudden inflammation of the pancreas. Symptoms of acute pancreatitis include severe abdominal pain that may radiate to the back. The pain may or may not be accompanied by nausea and vomiting. Patients who feel severe stomach pain that does not go away should seek prompt medical attention.
The FDA is investigating whether incretin mimetics may increase the risk for pre-cancerous changes in the pancreas called pancreatic duct metaplasia. These drugs may also increase the risk for thyroid cancer.
Exenatide may cause new or worse problems with kidney function, including kidney failure. Patients with severe kidney problems should not use this drug.
DPP-4 Inhibitors (Gliptins)
Dipeptidyl peptidase-4 (DPP-4) inhibitors, also called gliptins, are the second class of incretin drugs. They include sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).
DPP-4 inhibitors work in a similar way to GLP-1 inhibitors. However, unlike exenatide, which is given by injection, DPP-4 inhibitor drugs are taken as pills. They can be used alone or in combination with another oral diabetes drug (metformin, thiazolidinediones, or sulfonylureas).
These drugs are also available as two-in-one pills:
- Janumet and Janumet XR are two-in-one pills that combine sitagliptin with metformin
- Juvisync is a two-in-one pill that combines sitagliptin with the cholesterol drug simvastatin
- Jentadueto combines linagliptin and metformin
- Kombiglyze XR combines saxagliptin and metformin
- Kazano combines alogliptin and metformin, and Oseni combines alogliptin and the thiazolidinedione drug pioglitazone
Like GLP-1 inhibitors, DPP-4 inhibitors do not cause weight gain, have low risks for hypoglycemia, and have few severe side effects. The most common side effects include upper respiratory tract infection, sore throat, and diarrhea.
These drugs may increase the risk of acute pancreatitis (inflammation of the pancreas). Patients should be monitored for signs of pancreatitis after treatment begins or if the dosage is increased. The FDA is investigating whether incretin mimetics, which include GLP-1 inhibitors and DPP-4 inhibitors, may increase the risk for pre-cancerous changes in the pancreas (pancreatic duct metaplasia).
Sodium-glucose co-transportor 2 (SGLT2) inhibitors are a new class of diabetes drugs. In 2013, the FDA approved the first of these drugs, canagliflozin (Invokana) for treatment of adults with type 2 diabetes. The drug helps lower blood glucose levels by blocking the kidney’s reabsorption of glucose.
Canagliflozin can be used alone or in combination with other types of diabetes drugs (metformin, sulfonylurea, pioglitazone, insulin). It should not be used by patients who have diabetic ketoacidosis or severe kidney impairment.
Common side effects include vaginal yeast infection and urinary tract infections. During the initial months of treatment, this drug may cause decreased blood pressure and dizziness when standing up (orthostatic hypotension).
Pramlintide (Symlin) is an injectable drug that may help patients who take insulin but still need better blood sugar control. Pramlintide is a synthetic form of amylin, a hormone that is related to insulin. Pramlintide is used in combination with insulin to lower blood sugar levels in the 3 hours after meals.
Dopamine Agonists (Cycloset)
Bromocriptine mesylate (Cycloset) is an oral drug that may help improve blood sugar control in addition to diet and exercise. Bromocriptine helps boost levels of dopamine, a nerve chemical (neurotransmitter). Bromocriptine is used in other formulations, and usually in higher doses, for treatment of Parkinson’s disease. Common side effects may include nausea, vomiting, headache, dizziness, and fatigue.
Insulin replacement may be necessary when natural insulin reserves are depleted. It is typically started in combination with an oral drug (usually metformin).
Because type 2 diabetes is progressive, many patients eventually need insulin. However, when a single oral drug fails to control blood sugar it is not clear whether it is better to add insulin replacement or a second or third oral drug.
Some doctors advocate using insulin as early as possible for optimal control. However, in patients who still have insulin reserves, there is concern that extra natural insulin will have adverse effects. Low blood sugar (hypoglycemia) and weight gain are the main side effects of insulin therapy. It is still not clear if insulin replacement improves survival rates compared to oral drugs, notably metformin.
Forms of Insulin. There are two main insulin types:
- Fast-Acting Insulins for Surges. Insulin lispro and aspart are fast-acting insulins. They mimic insulin's response to food intake. They are taken before meals, and their short action reduces the risk for hypoglycemia afterward.
- Slower Insulins for Base Levels. Intermediate forms (including NPH and lente) and long-acting forms (glargine, ultralente) were developed to provide a steady level of insulin throughout the day. To date, glargine (Lantus) seems to be the most successful in achieving this goal in type 2 diabetes.
In general, there is no advantage to dosing insulin more than two times a day for patients with type 2 diabetes.