Many types of anti-hyperglycemic drugs are available to help people with type 2 diabetes control their blood sugar levels. Most of these drugs are aimed at increasing sensitivity to the person's own natural stores of insulin or boosting the person's own insulin production. Guidelines for the optimal use of these medications are changing rapidly.
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, providers should add a second drug rather than trying to push the first drug dosage to the highest levels.
Metformin (Glucophage and generic) is a biguanide, which works by reducing glucose production in the liver and by making tissues more sensitive to insulin. Providers recommend it as a first choice for most people 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 people who are obese 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 may include:
- A metallic taste.
- Gastrointestinal problems, including nausea and diarrhea (common, often improves over time or with lower doses).
- Interference with the absorption of vitamin B12 and folic acid.
- Lactic acidosis is a rare potentially life-threatening side effect. Major studies, however, have 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 certain kinds of heart failure or kidney or severe liver disease. Kidney disease and gastrointestinal side effects are the main reason for stopping this medication.
Sulfonylureas are oral drugs that stimulate the pancreas to release insulin. These medications were the second line diabetes treatment for years, but this is changing because they are more likely to cause weight gain and low blood sugar. A number of brands are available including chlorpropamide (Diabinese and generic), tolazamide (Tolinase and generic), glipizide (Glucotrol and generic), tolbutamide (Orinase and generic), glyburide (Micronase and generic), and glimepiride (Amaryl and generic). For adequate control of blood glucose levels, the drugs should be taken 20 to 30 minutes before a meal.
Most people can take sulfonylureas for 7 to 10 years before they lose effectiveness. Combinations with small amounts of insulin or other oral anti-hyperglycemic drugs (metformin or a thiazolidinedione) may extend their benefits. A combination of glyburide and metformin in 1 pill (Glucovance) is available.
Side Effects and Complications
In general, women who are pregnant or nursing or individuals who are allergic to sulfa drugs should not use sulfonylureas. Side effects may include:
- Hypoglycemia is the most common side effect. It is more likely with chlorpropamide and glyburide because they stay in your body for a longer period of time. Care should be taken during and after exercise.
- Weight gain (some sulfonylureas, such as glimepiride, may produce less weight gain than others)
- Water retention
- Some sulfonylureas may pose a slight risk for cardiac events.
- 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 glimepiride, 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 people must inform their provider 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 and generic). These drugs are rapidly metabolized and short-acting and therefore have a lower risk of hypoglycemia. If taken before every meal, they tend to mimic the normal effects of insulin after eating. People, then, can vary their meal times with this drug. These drugs often used in combination with metformin or other drugs.
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 and 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). These are the most powerful medication to increase insulin sensitivity in the liver.
Thiazolidinediones can have serious side effects. They can increase fluid build-up, which can cause or worsen heart failure in some people and often leads to water retention and swelling (edema) in the feet and legs. Combinations with insulin increase the risk. People with heart failure should not use them. People with risk factors for heart failure should use these drugs with caution.
In particular, there have been concerns that rosiglitazone increases the risks for heart attack and heart failure and should be restricted to only certain people. In 2013, the FDA lifted these restrictions, citing studies that indicated the drug posed no heightened risk for heart attack or death.
Thiazolidinediones may cause more weight gain than other diabetes medications or insulin. Any person who has sudden weight gain, water retention, or shortness of breath should immediately call their provider. Thiazolidinediones can also cause liver damage. People who take these drugs should have their liver enzymes checked regularly.
Other health concerns associated with thiazolidinediones included possible increased risks for:
- Bone fracture
- Bladder cancer
- Development or worsening of the eye condition diabetic macular edema
Alpha-glucosidase inhibitors, including acarbose (Precose and 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.
Because this class of drugs does not work as well as others, they are not preferred second-line treatments.
These medications need to be taken with meals. Unfortunately, about a third of people 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 person receives 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 MIMETICS (EXENATIDE, LIRAGLUTIDE, ALBIGLUTIDE, SEMAGLUTIDE, AND DULAGLUTIDE)
Incretin mimetics belong to a class of drugs that help improve how much insulin the body can make. Incretins are natural hormones that come from the gut and include glucagon-like peptide-1 (GLP-1) agonists and DPP-4 inhibitors.
GLP-1 agonists are given by injection and are prescribed for people with type 2 diabetes who have not been able to control their glucose with metformin. They can be taken in combination with other drugs or alone. Recent studies have shown beneficial effects of these medications to reduce the risk of cardiovascular disease
Exenatide (Byetta) was the first GLP-1 agonist drug. 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 agonist that is injected once a day. Albiglutide (Tanzeum) is another GLP-1 agonist.
Dulaglutide (Trulicity) and semaglutide (Ozempic) are long-acting drugs in this class of medicines that need to be given only every week. It can be given with several of the other oral agents.
The first of these medications available as an oral medication is also now available (semaglutide).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 or insulin. There does not appear to be a risk for hypoglycemia when they are used along with metformin.
Other side effects may include nausea, which usually disappears after about a week. Exenatide may cause new or worse problems with kidney function, including kidney failure. People with severe kidney problems should not use this drug.
There have been safety concerns that incretin mimetics may be associated with pancreatitis (inflammation of the pancreas) and pancreatic cancer. In 2014, the US FDA and the European Medicines Agency released a joint assessment that these drugs do not appear to cause pancreatic conditions. Regardless, these drugs are often not used for those with a history of pancreatitis.
DPP-4 INHIBITORS (GLIPTINS)
Dipeptidyl peptidase-4 (DPP-4) inhibitors, also called gliptins, are the second class of drugs that work through the incretin pathway. Drugs available in the United States from this class include sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).
DPP-4 inhibitors work in a similar way to GLP-1 mimetics except they use the body's own incretins. However, unlike GLP-1 mimetics, which are 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 may also be available as 2-in-1 pills, combined with metformin, simvastatin, or pioglitazone.
Like GLP-1 inhibitors, DPP-4 inhibitors do not cause weight gain, have low risks for hypoglycemia, and have few severe side effects. Side effects are uncommon, but may include upper respiratory tract infection, sore throat, and diarrhea. The FDA has recently warned that DPP-4 inhibitors may cause severe and disabling joint pain that is relieved soon after discontinuing these drugs.
The FDA is reviewing possible heart failure risks associated with saxagliptin.
Sodium-glucose co-transporter 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. Other SGLT2 inhibitors include dapagliflozin (Farxiga), empagliflozin (Jardiance), and ertugliflozin (Steglatro). These drugs help lower blood glucose levels by blocking the kidney's reabsorption of glucose. Recent studies have shown beneficial effects of these medications to reduce the risk of cardiovascular disease.
SGLT2 inhibitors can be used alone or in combination with other types of diabetes drugs (metformin, sulfonylurea, pioglitazone, and insulin). They should not be used by people who have DKA. The use of these medications in people with moderate-to-severe kidney impairment is still being studied. The FDA is reviewing possible heart risks associated with dapagliflozin and whether this drug increases the risk for bladder cancer.
In general, they are considered to be second or third line agents for treatment of type 2 diabetes.
Common side effects include vaginal yeast infection and urinary tract infections. During the initial months of treatment, this drug may cause dehydration, which can lead to decreased blood pressure and dizziness when standing up (orthostatic hypotension). A recent warning issued by the FDA states that SGLT2 inhibitors may also increase the risk for ketoacidosis.
Pramlintide (Symlin) is an injectable drug that is only approved for people who take insulin also 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 the level of dopamine, a nerve chemical (neurotransmitter). Bromocriptine is used in other formulations, and usually in higher doses, for treatment of Parkinson disease. Common side effects may include nausea, vomiting, headache, dizziness, and fatigue.
Insulin replacement may be necessary when natural insulin reserves are depleted, or insulin resistance cannot be overcome with oral medications. It is typically started in combination with an oral drug (usually metformin). In most cases, this should no longer be the second choice medication after metformin.
Because type 2 diabetes is progressive, many people 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 providers advocate using insulin as early as possible for optimal control. However, in people 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
The two main insulin types are classified by the speed and duration of their glucose-lowering effects:
- Fast-acting insulins for covering increased blood glucose due to meals. Insulin lispro, glulisine, and aspart are fast-acting insulins. They mimic insulin's response to food intake. They are taken immediately before meals, and their short action reduces the risk for hypoglycemia afterward.
- Short-acting insulins include regular insulin and velosulin for use with an insulin pump. They act slightly slower than fast-acting insulins and are taken within 1/2 to 1 hour before meals.
- Slower insulins include intermediate forms (NPH) and long-acting forms (glargine, detemir, and degludec), which were developed to provide a steady level of insulin throughout the day. To date, glargine (Lantus) and detemir (Levemir), and degludec (Tresiba) seems to be the most successful in achieving this goal in type 2 diabetes.
- For people with severe insulin resistance who need high doses of insulin there are a number of forms of concentrated insulin including U-300 (Toujeo) which is 3 times as concentrated and U-500 which is 5 times as concentrated.