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Best Treatments for Type 2 Diabetes

We compare the safety, effectiveness, and price of the most common drugs for this condition

Last updated: February 2018

Background

Type 2 diabetes is one of the most serious medical conditions affecting the U.S. An estimated 30.3 million people in the U.S., or about 9.4 percent of the population, have diabetes. That’s up from 2.5 percent of the population in 1980.

The disease is still most common among older people, affecting nearly a quarter of those 65 or older. But over the past 20 years, it's become more common in young people, too, as the percentage of young people who are sedentary and overweight has skyrocketed.

Despite widespread attention to the diabetes epidemic, about one in three people who have diabetes—some 10 million people—don't know they have it. And those that do often aren't adequately treated. At least a quarter of people who diagnosed with diabetes get the medical care, including drugs, that are proved effective.

Why is diabetes a concern?

Having diabetes more than doubles the risk of developing and dying of heart disease and other problems. Indeed, the condition is as potent a predictor and risk factor for heart disease and heart attack as are cigarette smoking, high blood pressure, and high cholesterol.  

Diabetes also raises the risk for a host of other problems. These include: stroke, nerve damage, kidney damage; damage to the eye as well as total blindness; impotence, poor wound healing, decreased circulation in the legs and feet, and susceptibility to infections that can worsen and require amputations.

In addition, people with diabetes are likely to have other dangerous health conditions. One in five people 35 and older who have diabetes also have heart disease. And one study found that 47 percent of people with diabetes had two or more other heart disease risk factors—such as smoking, high blood pressure, high cholesterol, and physical inactivity.

Overall, diabetes is the seventh leading cause of death in the U.S. It is also a leading cause of disability. African-Americans, Asian-Americans, Hispanics, American Indians, and the indigenous people of Alaska are more prone to develop diabetes (due to genetic and environmental factors) and to become disabled or die from it, partially because they they are less likely to get good care.

Doctors once thought that type 2 diabetes happened only in older people. But studies over the last decade show it can develop at any age. Children and adolescents in high risk families are developing type 2 diabetes at higher rates in recent years, making routine screening even more important.  

Proper treatment can keep people with diabetes healthy. In fact, all people with diabetes who receive proper and consistent care live a high quality of life, and can work and carry out daily activities.

Symptoms and Getting Tested

The symptoms of type 2 diabetes tend to develop gradually and might go unnoticed. When symptoms do occur, they usually include:

  • Fatigue
  • Blurred vision
  • Frequent urination
  • Numbness or tingling in your hands or feet
  • Increased thirst and hunger
  • Infections and slow healing of wounds
  • Weight loss

These symptoms can also be mild and intermittent for years. If you experience any of them—and especially if you experience two or more, for even a few days—you should see a doctor.

In the early stages of the disease, most people don't experience symptoms. Yet, the damage to organs occurs even in the absence of symptoms. That's why it’s important for people who may be at risk for diabetes to get their blood sugar levels checked regularly. Those at risk include:

  • People 45 and older who have a history or diagnosis of heart or cardiovascular disease, are overweight or obese or physically inactive
  • People of any age who have high blood pressure; high cholesterol or triglyceride levels; a history of prediabetes (see below); a condition known as polycystic ovarian syndrome
  • Anyone with a parent or a sibling who has diabetes
  • African-Americans, Hispanic-Americans, Asian Americans, Native Americans, Pacific Islanders, or Alaskan Natives
  • Women who have had diabetes during pregnancy or a baby weighing more than 9 pounds at birth.

If you are in one of these groups and have never had a blood sugar check, get tested as soon as possible. The test is easy and can be done at the same time as other routine tests, such as a cholesterol test. It's important that you know your blood test results, so you can understand if you are at risk for, or have, diabetes.

Medical experts don't all agree exactly how often adults should have a diabetes test. The American Diabetes Association advises that everyone aged 45 and over have a blood sugar test once every three years. But the highly regarded U.S. Preventive Services Task Force says not enough scientific evidence exists to show that such broad screening, for adults or children, has benefits or is worth the cost.

Ultimately, the decision rests with you and your doctor, and depends on an assessment of your overall health, risk factors, weight, and family history. Some doctors are inclined to check the blood sugar levels of most people over age 45 or 50, especially if they are 10 or more pounds overweight. Other doctors may be more conservative.

Two major blood tests diagnose diabetes

Blood sugar tests are inexpensive and easy, though they may have to be done a few times to yield a conclusive diagnosis. The most recommended test is done after an overnight fast. If your blood sugar is 126 milligrams per deciliter (mg/dl) or greater after being checked twice, you are considered to have diabetes. Another type of test can be done at any time (not just after an overnight fast). If this test indicates your blood sugar level is 200 mg/dl or above, and if you have symptoms, then you are considered to have diabetes.

Your doctor may also talk to you about a blood test known as “hemoglobin A1c”, usually abbreviated in print as HbA1c. This is a commonly used test to evaluate blood sugar control after treatment is started. But your doctor may order this test to make the diagnosis in the first place. There’s more about this measure in the next section.

Type 1 Vs. Type 2 Diabetes

Diabetes is a marked by high blood glucose (a sugar) largely caused by decreased production of the hormone insulin and/or increased resistance to the action of insulin by certain cells.

Glucose is one the body’s main fuels. When you eat carbohydrates (pasta, bread, rice, grains, fruits, and vegetables), your digestive system breaks them down into glucose, which is released into the bloodstream so your body can use it for energy. Glucose also gets stored in the liver and muscles as glycogen, which can later be broken down back into glucose when the body needs fuel.

Insulin, which is produced in the pancreas, regulates both the movement of glucose into the body’s cells and the breakdown in the liver of glycogen into glucose. Both actions are critical to keeping blood sugar levels within normal ranges.

Type 1 diabetes

Usually diagnosed in childhood or the early teen years, type 1 diabetes affects about 1.5 to 2 million people in the U.S., and increasingly adults as well. In this condition, the pancreas, over a relatively brief period of time, stops producing insulin. The onset of the disease is usually abrupt, with severe symptoms that require immediate attention.

Type 1 diabetes is an “autoimmune” disease, which means the body's immune system attacks specific organs, essentially attacking itself. Specifically, aberrant immune cells damage and destroy the part of the pancreas that produces insulin. In the case of type 1 diabetes, the body attacks the insulin-producing cells in the pancreas. Since the insulin producing cells are eventually totally destroyed, people with type 1 diabetes must inject insulin every day.

Type 2 diabetes

In this form of the disease, the pancreas produces enough insulin, at least in the early years. But for reasons that are still not well understood, the body’s cells become resistant or insensitive to it. To compensate, the pancreas pumps out increasing amounts of insulin to normalize blood glucose levels. Over time—as long as a decade—this ever-increasing production becomes unsustainable, and the pancreas’ ability to produce insulin declines.

As a result, the telltale marker of diabetes emerges: Glucose levels rise in the blood because it is unable to enter the body’s cells. The excess glucose damages the body’s tissue and leads to the symptoms and complications of diabetes. When the blood glucose level gets high enough, the sugar begins to appear in the urine and causes increased urination.

Elevated blood sugar puts a strain on many parts of the body. Over years, it is particularly toxic to the body’s blood vessels; it causes small vessels to weaken, for example in the eye and kidney, and larger vessels supplying the heart, brain and extremities to thicken. This leads to long-term complications.

Proper treatment that keeps blood sugar in the normal range, combined with aggressive treatment to keep blood pressure and cholesterol in normal range as well, sharply reduces the risk of complications.

There are many theories and ideas about the causes of type 2 diabetes. Studies show the disease runs in families, meaning it has a strong genetic component.

But the major reason diabetes has increased over the past 30 years is the increased prevalence of excess body weight and obesity, both of which are major factors in the development of insulin resistance. In the US, 85 percent to 90 percent of people with type 2 diabetes are overweight or obese.

What is Pre-Diabetes?

In the last decade, doctors and researchers have recognized that a large number of people in the U.S. have fasting blood sugar levels above 100 mg/dL, the upper limit of normal, but less than the 126 mg/dL required for a diagnosis of diabetes. The most recent estimate from the Centers for Disease Control and Prevention indicates that 34 percent of adults 20 and older—84 million people—have blood glucose levels in this range and could be considered to have "pre-diabetes." It’s also sometimes called borderline diabetes or impaired fasting glucose.

What concerns doctors is that a growing body of research now shows that people with pre-diabetes have both a high risk of developing diabetes, and an elevated risk of heart disease and stroke even if their fasting glucose level never rises above 126 mg/dL.

In an analysis involving 10,428 people in Australia, for example, those with pre-diabetes were found to have 2.5 times the risk of dying from heart disease over a 5-year period compared to people whose blood sugar was normal.

Such findings are leading some doctors to identify and treat people with pre-diabetes. But most doctors agree, and research backs it up, that dietary and lifestyle changes, with the main goal of losing weight, can be very effective for keeping pre-diabetes under control, and before any medication needs to be prescribed.

Lifestyle modifications have also become a mainstay of treatment for people with diabetes. Studies consistently show that lifestyle changes alone—especially weight loss in those who are overweight or obese—can prevent the complications of diabetes. For some people, these changes can eliminate or reduce the need for drugs.

Since many people with diabetes also have high blood pressure and/or high cholesterol, your doctor will aim to get those under control, too, using diet and lifestyle changes, and medicines if necessary.

Medication Basics

This report focuses on eight classes of diabetes medicines often used as first or second line treatment for adults with type 2 diabetes. Like all drugs, the names of the drug groups and the names of the individual medicines in those groups are not easy to pronounce or remember. We do our best to keep things simple but can’t avoid using these complex names.

Good to know: We do not evaluate insulin by itself since it's rarely used as an initial treatment for adults with type 2 diabetes. A small number of people may need insulin, especially if their blood sugar levels are very high and they are have symptoms, such as excessive urination, thirst or weight loss.

Below, the first table presents the groups of diabetes drugs, including those now available in combination form. The second table lists the individual drugs with their generic and brand names. We indicate whether the class has a generic available and whether an individual drug is available in generic form.

Type of Drug

Individual Drugs (Brand and generic names)

Available as a Generic?

Sulfonylureas

Brands: Amaryl, Diabeta, Glynase, Glucotrol, Glucotrol XL

Generics: Glimepiride, Glipizide, Glyburide

Yes
Biguanides

Brands: Glucophage, Glucophage XR

Generics: Metformin, Metformin XR

Yes
Thiazolidinediones

Brands: Actos, Avandia

Generics: Pioglitazone, Rosiglitazone

Yes
Alpha-Glucosidase Inhibitors

Brands: Precose, Glyset

Generics: Acarbose, Miglitol

Yes
Meglitinides

Brands: Prandin, Starlix

Generics: Nateglinide, Repaglinide,  

Yes
Dipeptidyl Peptidase 4 Inhibitors

Brands: Januvia, Onglyza, Tradjenta, Nesina

Generics: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin

Yes
Sodium-Glucose Co-Transporter 2 Inhibitors

Brands: Farxiga, Invokana, Jardiance

Generics: Dapagliflozin, Canagliflozin, Empagliflozin

Yes
Glucagon-Like Peptide-1 Receptor Agonists

Brands: Byetta, Bydureon, Victoza, Trulicity

Generics: Exenatide, Exenatide Long-Acting, Liraglutide, Dulaglutide

Yes
Combinations of Sulfonylureas Plus Metformin

Brands: Glucovance

Generics: Glyburide and Metformin combination

Yes
Other Combinations Brands: Actoplus Met, Avandamet, Janumet, Kombiglyze XR, Kazano, Jentadueto, Jentadueto XR*, Xigduo XR*, Invokamet, Invokamet XR*, Synjardy No

Generic Name

Brand Name(s)

Available as a Generic?

Thiazolidinediones    
Pioglitazone Actos Yes
Rosiglitazone Avandia Yes
Meglitinides    
Repaglinide Prandin Yes
Nateglinide Starlix Yes
Alpha-glucosidase Inhibitors    
Acarbose Precose Yes
Miglitol Glyset Yes
Biguanides    
Metformin Glucophage, Glucophage XR* Yes
Sulfonylureas    
Glyburide/ glibenclamide Diabeta, Glynase Yes
Glipizide Glucotrol, Glucotrol XL* Yes
Glimepiride Amaryl Yes
Dipeptidyl peptidase 4 Inhibitors    
Sitagliptin Januvia No
Saxagliptin Onglyza No
Linagliptin Tradjenta No
Alogliptin Nesina No
Sodium-Glucose Co-Transporter 2 Inhibitors    
Dapagliflozin Farxiga No
Canagliflozin Invokana No
Empagliflozin Jardiance No
Glucagon-Like Peptide-1 Receptor Agonists    
Exenatide Byetta, Bydureon No
Liraglutide Victoza No
Dulaglutide Trulicity No

*XR=extended release, XL=long-acting

Our evaluation of diabetes drugs is based largely on a comprehensive, independent review of the scientific research that examined 219 carefully selected studies. The 2016 review was conducted by a team of physician researchers at the Johns Hopkins University Evidence-based Practice Center. This team conducted the review as part of the Effective Health Care Program sponsored by the Agency for Healthcare Research and Quality, a federal agency.

The full report is available at www.effectivehealthcare.ahrq.gov/reports/final.cfm. The Johns Hopkins University Evidence-based Practice Center and the Agency for Healthcare Research and Quality are not responsible for the advice and recommendations in our report.

How the drugs work

The aim of treatment with lifestyle changes and medications is to lower your HbA1c (and keep it low), to reduce symptoms, and to reduce the risk of diabetes complications. 

The eight types of diabetes medicines work in different ways to achieve those goals. But they all act to lower blood sugar levels, help improve the body’s use of glucose, and decrease symptoms. It’s useful to know the basics:

  • The sulfonylureas and meglitinides increase the secretion of insulin by the pancreas.
  • Metformin inhibits sugar production by the liver and decreases insulin resistance.
  • The alpha-glucosidase inhibitors delay absorption of sugar by the intestine.
  • The thiazolidinediones decrease insulin resistance in muscle.
  • The dipeptidyl peptidase 4 inhibitors promote the release of insulin from the pancreas after eating a meal.
  • The glucagon-like peptide-1 receptor agonists promote the release of insulin from the pancreas after eating and may increase the feeling of fullness after eating.
  • The sodium-glucose co-transporter-2 inhibitors promote excretion of sugar in the urine.

Since the drugs work in different ways and can fail to control blood sugar levels adequately over time, they may be used in combination. More than 50 percent of people with diabetes who start taking one type of medicine will need another type (or insulin) within three years to keep their blood sugar under control.  

In addition, even if your blood sugar levels are very high when you are first diagnosed, and you are prescribed one or more medications, changing your lifestyle always helps.  

All adults with diabetes are also urged to undergo diabetes self-management education classes. Taking such classes has been shown to improve blood sugar control over time.

Evidence strongly supports the additive effect of lifestyle changes plus medicines. But several studies also show that many people with diabetes can lower their blood sugar levels almost as much with lifestyle changes alone as with medicines, especially in the early stages of their disease.

Treatment Goals

The aim of treatment with lifestyle changes and medications is to get your HbA1c lower, and keep it low, in order to reduce symptoms and to reduce the risk of the many diabetes complications.   

The HbA1c test is what your doctor will use to track how well your treatment is working. It measures glucose levels chemically bound to hemoglobin, a protein carried by red blood cells. Over time, high blood sugar levels cause more glucose to bind with hemoglobin, so a high HbA1c percentage indicates that blood sugar levels are high on average.

An HbA1c level below 7 percent is associated with a lower risk of diabetes complications, such as kidney disease and eye disease that can lead to blindness. And although some very long-term studies have shown similar benefits for heart disease and stroke, the studies have not been conducted over long-enough periods of time to yield conclusive results. Most have studied the effects of lower HbA1c for a year or less.

Aiming for an even lower HbA1c level—below 6.5 percent—that’s closer to the range found in healthy people has been promoted in the past, but recent studies are mixed on whether this is better for people with diabetes. The normal range for HbA1C is 4.5 to 5.7 percent.  

Given the evolving science, the American Diabetes Association and other diabetes experts now recommend that the vast majority of patients strive for an HbA1c of around 7 percent.  A higher HbA1c goal may be appropriate for certain patients, including those with a history of repeated episodes of low blood sugar, advanced diabetes complications (such as severe kidney disease or heart disease), extensive multiple chronic conditions or limited life expectancies.

Managing diabetes is quite complex. It requires careful, sometimes daily, attention to diet, monitoring blood sugar, and adjustment in medication doses. But small changes, such as losing 10 to 15 pounds, or exercising just 20 to 30 minutes several days a week, have been shown to yield benefits. Indeed, some people who lose weight and improve their diets are able to stop taking their their diabetes medicines.

Safety and Side Effects

All the diabetes medicines can cause side effects. These vary from drug class to drug class and medicine to medicine.   

Understandably, side effects can keep people from taking their diabetes treatments. On average, 10 to 20 percent of people with diabetes stop taking their pills due to side effects. It's important to discuss any side effects you experience with your doctor.

Since many people with diabetes are trying to lose weight, the weight gain that can occur with some diabetes medicines can be especially frustrating.

The box below gives an overview of side effects associated with various diabetes drugs. The potential side effects of each drug are discussed at length in the next section.

Side Effects of Oral Diabetes Drugs

Most of the side effects listed here ease over time or stop when the medication is discontinued. However, a few can be permanent in certain people

Common

  • Weight gain
  • Gastrointestinal side effects (abdominal pain, nausea, vomiting, diarrhea, gassiness, and bloating)
  • Edema (fluid in legs and ankles)

Uncommon

  • Hypoglycemia or low blood sugar (usually minor if caught in time but can be serious or fatal if not treated; symptoms include profuse sweating, tremor, shakiness, dizziness, hunger. When serious, includes mental confusion, coma, and risk of stroke or death)Congestive heart failure
  • Anemia (low red blood cell counts)
  • Allergic reactions
  • Urine infections
  • Yeast infections
  • Hip and non-hip fractures

Very Rare

  • Lactic acidosis (build up of acid in the blood)
  • Macular edema (eye problems)
  • Liver disease/liver failure
  • Pancreatitis (inflamed pancreas)
  • Cancer

Most notably, some diabetes drugs can cause low blood sugar, or hypoglycemia. This is a dangerous side effect and one that leads some doctors to prescribe one diabetes drug over another.

Unfortunately, some people do not experience minor symptoms to warn them that their blood sugar is getting dangerously low (called hypoglycemia). That’s one reason your doctor will emphasize that you must check your blood sugar regularly if you take a diabetes medicine that can cause low blood sugar.

Drug Effectiveness

The good news is that the diabetes drugs have been compared to each other in many good studies, and some of the drugs have been used for years and helped millions of people.  

The bad news is that most of the careful studies have not tracked the effects of the drugs over many years, which is critical for understanding the long term benefits as well as possible problems. Even so, the studies help clarify the benefits and adverse effects of most diabetes drugs, and signal typical and expected effects among people with diabetes.

Importantly, such studies do not reveal how a specific person with diabetes will respond to any particular drug. Only your doctor and you can decide precisely which drug or drug combination is best for you given your health status, weight, other medical needs, and severity of your diabetes. And only you and your doctor can track how well a particular drug or combination of drugs is helping you.

Our evaluation leads to the following overall conclusions:

Metformin is a superior drug based on the available evidence. This medicine lowers HbA1c the same amount or more than other diabetes drugs, does not cause weight gain, decreases cardiovascular mortality more than sulfonylureas, and appears to have the best safety profile when comparing serious side effects in people who do not have kidney, liver, or heart disease. As further discussed below, however, certain patients should not take metformin.

Taking two diabetes drugs can have a positive additive effect on reducing HbA1c. This is a major plus for the many people with diabetes whose blood glucose is not well controlled by taking just one drug. The downside is that taking two drugs poses a higher risk of side effects. However, if you take lower doses of each drug, the added risk of side effects can be reduced.

Newer drugs are more expensive. The newer diabetes medicines can cost substantially more than the older ones.  

Blood sugar (HbA1c) reductions are generally similar across drugs, except dipeptidyl peptidase-4 inhibitors and alpha-glucosidase inhibitors ,which have a smaller effect. SGLT-2 inhibitors are also generally weaker than metformin, SU, TZDs, or GLP agonists.

Diabetes drugs have differing effects on weight. Body weight was decreased or maintained with metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, alpha-glucosidase inhibitors, and sodium-glucose co-transporter 2 inhibitors.

In relatively short-term studies, the greatest weight loss was experienced by people taking a glucagon-like peptide 1 receptor agonist or a sodium-glucose co-transporter-2 inhibitor.  

Weight increased with sulfonylureas, thiazolidinediones, and meglitinides. The differences seen between drugs was up to 11 pounds.

Each drug class has specific side effects, and less is known about the safety of the newer medications. The diabetes drugs have distinctly different “safety profiles.” This factor may be one of the primary drivers of your and your doctor’s decision for initial and on-going treatment.

For example, the evidence clearly shows that the sulfonylureas pose a higher risk of hypoglycemia than most other oral diabetes medications except repaglinide (Prandin). Sulfonylureas also pose a higher hypoglycemia risk compared with the injectable medication class of glucagon-like peptide 1 receptor agonists. 

Several combinations of injectables (glucagon-like peptide-1 receptor agonists, basal insulin, and premixed insulins) added to metformin showed varying risks for hypoglycemia. The combination of metformin plus a glucagon-like peptide-1 receptor agonist had a lower risk of hypoglycemia than the combination of metformin plus either premixed or basal insulin.  

Minor but annoying side effects may also play a role in your and your doctor’s choice of a diabetes medicine or medicines. For example, gastrointestinal side effects—including bloating, gas, nausea, vomiting and diarrhea—are very frequent with acarbose and glucagon-like peptide-1 receptor agonists. They occur less with metformin.

Advantages and Disadvantages of Select Diabetes Drugs

Advantages:

Disadvantages:

Sulfonylureas (glyburide, glimepiride, glipizide)  
  • Fast onset of action
  • No effect on blood pressure
  • Convenient dosing
  • Low cost
  • Lower risk of GI side effects than metformin
  • Weight gain (5 to 10 pounds on average)
  • Heightened risk of hypoglycemia
  • Glyburide has slightly higher risk of hypoglycemia compared with glimepiride and glipizide
Metformin  
  • Low risk of hypoglycemia
  • Not linked to weight gain
  • No effect on blood pressure
  • Low cost
  • Higher risk of GI side effects (nausea and diarrhea)
  • Cannot be taken by people with diabetes who have moderate or severe kidney  disease or heart failure because of risk of lactic acid build-up
  • Less convenient dosing
Alpha-Glucosidase Inhibitors (acarbose, miglitol)  
  • Slightly lower risk of hypoglycemia compared to sulfonylureas
  • Not associated with weight gain
  • Decreases triglycerides
  • Less effective than most other diabetes pills in lowering HbA1c
  • Higher risk of GI side effects than other diabetes pills except metformin
  • Inconvenient dosing
Thiazolidinediones (Actos, Avandia)  
  • Low risk of hypoglycemia
  • Decreased blood pressure
  • Convenient dosing
  • Higher risk of heart failure
  • Weight gain (5 to 10 pounds)
  • Linked to higher risk of edema (fluid build-up)
  • Increase in “bad” (LDL) cholesterol
  • Avandia linked to higher risk of heart attack
  • Actos linked to increased risk of bladder cancer
  • Slower onset of action
  • Rare risk of liver problems; requires monitoring
  • Linked to increased risk of upper and lower limb fractures
Meglitinides (nateglinide, repaglinide)  

  • Rapid onset of action
  • Repaglinide associated with risk of hypoglycemia and weight gain similar to sulfonylureas
  • Nateglinide has less effect on HbA1c
  • Inconvenient dosing
Dipeptidyl Peptidase-4-inhibitors (Januvia, Onglyza, Tradjenta, Nesina)  
  • Low risk of hypoglycemia
  • Few known side effects (but they are newer drugs)
  • Lower risk of GI side effects than metformin
  • No weight gain
  • Helps kidney function in people with kidney damage
  • Convenient dosing
  • Associated with pancreatitis or inflammation of the pancreas
  • Reduce HbA1c less than other diabetes drugs
  • May only be valuable as second drug
  • Increased risk of heart failure
  • Can cause joint pain
  • May cause skin rash
Sodium-Glucose Co-Transporter-2 Inhibitors (Farxiga, Invokana, Jardiance)
 
  • Greater weight loss compared with metformin or DPP-4 inhibitors (3 to 6 pounds)
  • Decreases blood pressure
  • Low risk of hypoglycemia
  • Greater risk of urinary tract and yeast infections in men and women
  • Less data on potential side effects compared to older medications
Glucagon-Like Peptide-1 Receptor Agonists (Byetta, Bydureon, Victoza, Tanzeum, Trulicity)
 
  • Low risk of hypoglycemia
  • Greater weight loss compared with sulfonylureas, metformin and DPP-4 inhibitors (about 5 pounds)
  • Decreases blood pressure
  • Convenient dosing
  • Reduces risk of death in people who have known heart disease
  • Associated with pancreatitis or inflammation of the pancreas
  • Greater risk of nausea, vomiting and diarrhea compared to metformin
  • Injectable medication only
  • Less data on potential side effects compared to older medications
  • Increased risk of gall bladder problems

1. Bennett WL, et al, Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update. Comparative Effectiveness Review No. 27. March 2011 (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No. 290-02-0018.) AHRQ Publication No. 11-EHC038-EF. Rockville, MD: Agency for Healthcare Research and Quality. March 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

2. Bennett WL., et al, Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Int Med. (May 3 2011); Web published in advance of print publication, March 14, 2011.

Other Rare Side Effects


Heart Risk

Results from multiple studies prior to 2007 found that Avandia (rosiglitazone) was associated with an increased risk of heart attack and stroke. In 2007, the FDA announced major restrictions on the use of Avandia. Yet, as newer studies came out, in 2015, the FDA eliminated all restrictions on Avandia, indicated the benefits of the drug may exceed its risks.

The story behind this sharp change is too complex for this report. We still advise that you discuss the heart attack and stroke risk of Avandia with your doctor if he or she prescribes it.

Avandia and Actos pose an elevated risk of heart failure, too. Between 1 and 3 people in 100 without a history of heart disease will develop the condition if they take one of these drugs. Because of this risk, the FDA has placed  “black box” warning on the labels of both Actos and Avandia.

In contrast, metformin and the sulfonylureas do not raise the risk of heart failure in a significant way compared to the general risk of this condition among people with diabetes, which is higher than normal.

A U.S. Food and Drug Administration (FDA) safety review found that type 2 diabetes medicines containing saxagliptin and alogliptin (both dipeptidyl peptidase-4 inhibitors) may increase the risk of hospitalization for heart failure, particularly in patients who already have heart or kidney disease. The FDA also added a warning to their labels. Whether this is true for all drugs in this class or whether this only pertains to those at higher risk for heart failure is still unclear.

If you take one of these medicines (Actos, Avandia, saxagliptin, or alogliptin) and have swelling of any part of your body, sudden weight gain, or breathing problems, you should contact your doctor immediately.

Fractures

Both Actos and Avandia have been linked to a slightly increased risk of fractures of the upper and lower limbs, such as the wrist or ankle, in women. The risk was small—about 2 percent higher in people taking Avandia or Actos, compared with those taking other diabetes drugs.

Bladder cancer

Actos has also been shown to increase the risk of bladder cancer in people who take it for a year or longer. The risk applies to all drugs containing pioglitazone, including Actoplus Met, Actoplus Met XR, and Duetact. Because of this, France banned Actos and combination pills and Germany has recommended that pioglitazone no longer be started in patients not already being treated with this medication.

People who have previously had or currently have bladder cancer should not use Actos or the combination pills that contain it at all.

If you’re on Actos, be alert for signs of bladder cancer, which include blood or red color in your urine, urgent need to urinate or pain while urinating, and pain in your back or lower abdomen. Contact your doctor if you experience any of those symptoms.

Macular Edema

Actos and Avandia have been associated with new or worsening of macular edema—the build up of fluid in the back of the eye—causing vision impairment that can become permanent. If you take one of these treatments, be sure you receive regular diabetic eye care and if you experience any new vision problems, be referred to an ophthalmologist as soon as possible.

Metformin and Lactic Acidosis

Metformin has been associated with rare occurrences of lactic acidosis—a build-up of lactic acid in the blood that can be fatal. This extremely rare risk appears to exist mostly for people with diabetes who also have moderate to severe kidney disease. Based on years of data suggesting that metformin appears safe in persons with mild to moderate kidney disease, the FDA recently loosened its restrictions on metformin. The agency now says that metformin can be safely used in patients with moderate kidney failure, but shouldn’t be used with more advanced levels of kidney failure.   

Metformin also lower vitamin B12 levels and some doctors may recommend you take a B12 supplement if you take this medicine.

Pancreatitis

The FDA says there have been reports of inflammation of the pancreas, which can lead to permanent damage or even death, with the dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists. In addition, an increased risk of gall bladder disease and gall stones has been reported. These medications should not be used in patients with a history of pancreatitis or gall stones.  

Anyone taking a glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase-4 inhibitor who develops persistent severe abdominal pain should stop the medication and contact your physician immediately.

Ketoacidosis

The newest class of medications, the SGLT-2 inhibitors, has recently been associated with ketoacidosis, a life-threatening build-up of acid in the blood. Patients with risk factors for ketoacidosis (such as pancreatitis and alcohol abuse) should not take SGLT-2 inhibitors. Patients taking SGLT-2 inhibitors should be monitored for ketoacidosis.   

Kidney Failure and Dehydration

The GLP-1 RA’s and SGLT-2 inhibitors can lead to dehydration, and in rare cases, kidney failure. Be sure to tell your doctor if you become dehydrated and/or feel weak and dizzy. And drink plenty of fluids when you are taking them.

The SGLT-2 inhibitors also can increase urination. Sometimes this can cause people to feel dizzy or weak and become dehydrated.

Yeast and Urinary-Tract Infections

The SGLT-2 inhibitors (Farxiga, Invokana, Jardiance) increase the risk of genital yeast infections for both men and women. About 1 to 7 percent of men, and 3 to 18 percent of women, taking an SGLT-2 inhibitor can expect to develop a genital yeast infection, compared with 0 to 2 percent of men and 1 to 4 percent of women taking any other diabetes drug.

SGLT-2 inhibitors also increase the risk of urinary tract infections, including potentially life-threatening ones.

Our Recommendations

Taking effectiveness, safety, side effects, dosing, and cost into consideration, if you and your doctor decided that you need medicine to control your diabetes, we recommend the following as first-choice treatments, along with diet and lifestyle changes as suggested by your physician.

Metformin and Metformin Sustained-Release—alone or with glipizide or glimepiride

Glipizide and Glipizide Sustained-Release—alone or with metformin

Glimepiride—alone or with metformin

All these medicines are available as low-cost generics, either alone or in combination. Many of these recommendations are available, for example, as discounted generic drugs at various chain drugstores around the U.S. At Walmart for, example, we found various strengths of glimepiride, glipizide and metformin for $4 for a month's supply or $10 for a three-month's supply.

In recent years, a strong medical consensus has emerged in the U.S., Europe, and Australia that most newly diagnosed people with diabetes who need a medicine should first be prescribed metformin.

Based on the in-depth evaluation of diabetes drugs on which this report is based, we agree with that advice. Unless your health situation prevents it, consider trying metformin first. If metformin fails to bring your blood glucose into normal range, you may need a second drug. Most commonly that should be one of the two other recommended drugs.

If you are unable to take metformin or do not tolerate it well, you face a choice of one of the sulfonylureas or a newer medicine as your first line medicine. Despite the elevated risk of hypoglycemia, we recommend trying glipizide or glimepiride. If glipizide or glimepiride alone fail to bring your blood glucose into control and keep your HbA1c at or below 7 percent, your doctor will likely recommend a second drug.

If upon initial diagnosis your glucose and HbA1c are quite high, you may be prescribed a combination of two drugs at the beginning of treatment—usually metformin plus a sulfonylurea.

How We Made Our Recommendations

Our evaluation is based in large part on an independent review of the scientific evidence on the effectiveness, safety, and adverse effects of the diabetes medicines conducted by the Johns Hopkins University-evidence based Practice Center with the Agency for Healthcare Research and Quality. This analysis reviewed hundreds of studies, including those conducted by the drugs’ manufacturers. A synopsis of the results of this analysis, written by the researchers at Johns Hopkins, forms the basis of portions of this report.


However, no statement in this report should be construed as the official position of the Johns Hopkins Evidence-based Practice Center, the Agency for Healthcare Research and Quality, or the U.S. Department of Health and Human Services. In particular, none of those entities played any role in our recommendations. Consumer Reports, publishers of Consumer Reports Best Buy Drugs, is solely responsible for those, and for all other specific advice and recommendations in this report.


An earlier version of this report from 2012 relied on additional sources listed here:


-An analysis of selected classes of diabetes drugs conducted by the Drug Effectiveness Review Project (DERP), an initiative to evaluate the comparative effectiveness and safety of hundreds of prescription drugs


-Three reviews of oral diabetes drugs by the Cochrane Collaboration


-An American Medical Association monograph on the oral diabetes drugs


-A Veteran’s Administration monograph on diabetes drugs


-Recent guidelines issued by the American Diabetes Association and American College of Cardiology


-Selected recent articles in peer-reviewed journals (See References)


Consumer Reports recommendations used the following criteria. The drug had to:


-Be as effective or more effective than other oral diabetes medicines


-Have a safety record equal to or better than other oral diabetes medicines


-Cost roughly the same or less than other oral diabetes medicines


References

1. 52-week add-on to Metformin Comparison of Saxagliptin and Sulphonylurea, With a 52-week Extension Period. Study NCT00575588, accessed 9 May 2011 http://clinicaltrials.gov/ct2/show/results/NCT00575588term=saxagliptin&rslt=With&rank=12&sect=X3870615#evnt.

2. “A randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes.” The UK Prospective Diabetes Study Group. Diabetes Care (1998): Vol 21 (1), pages 87-92.

3. American Diabetes Association, Type 2 Diabetes Basics. Accessed December 21, 2012 http://www.diabetes.org/diabetes-basics/type-2/

4. American Diabetes Association: Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2007 30: S42-47.

5. Amori, R.E. et al, “Efficacy and safety of incretin therapy in type 2 diabetes — systematic review and meta-analysis,” JAMA (July 11, 2007): Vol. 298, No. 2, pages 194-206.

6. Barr, E.L. et al, “Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose and impaired glucose tolerance,” The Australian Diabetes, Obesity, and Lifestyle Study. Circulation (July 10, 2007). Vol. 116.

7. Bennett W.L., et al, Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update. Comparative Effectiveness Review No. 27. March 2011 (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No. 290-02-0018.) AHRQ Publication No. 11-EHC038-EF. Rockville, MD: Agency for Healthcare Research and Quality. March 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

8. Bennett W.L., et al, Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Int Med. (May 3 2011); Web published in advance of print publication, March 14, 2011.

9. Burnet, D.L. et al, “Preventing diabetes in the clinical setting,” J. Gen Int. Med. (2006) Vol. 21, pages 84-93.

10. Chobanian, A.V. et al, “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report.” JAMA (2003): Vol. 289(19), pages 2560-2572.

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Editor's Note:

These materials are made possible by a grant from the state Attorney General Consumer and Prescriber Education Grant Program, which is funded by the multi-state settlement of consumer-fraud claims regarding the marketing of the prescription drug Neurontin (gabapentin).



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