Non-insulin drugs for treating type 2 diabetes

When a person has type 1 diabetes, it means that their body has stopped producing insulin. As a result, they need to either use an insulin pump or inject the hormone several times per day.

For people with type 2 diabetes, doctors generally recommend other medications first. When recommending courses of treatment, doctors consider several factors, such as:

• blood sugar levels, including A1C levels
• overall progress on blood sugar management
• treatment history
• weight
• age
• medical history
• other ongoing health issues

Most people with mild to moderate type 2 diabetes can manage the condition with oral medications or non-insulin injectable drugs, as well as lifestyle and dietary strategies.

Some people can even manage the condition with lifestyle strategies alone. These may include dietary changes, regular exercise, and efforts to manage their weight.

However, a doctor may prescribe insulin for people who have severe symptoms of type 2 diabetes or certain accompanying medical conditions.

Typically, a doctor will recommend insulin when a combination of non-insulin drugs is no longer enough to manage a person’s blood sugar levels.

A wide variety of non-insulin medications are available for people with type 2 diabetes, and new drugs emerge every year.

The following are some of the most common oral treatment options.

Metformin

For people with type 2 diabetes, doctors usually prescribe metformin (Glucophage) first.

Metformin helps a person manage their blood sugar levels by reducing the amount of sugar the liver produces and improving how the body uses the sugar.

Metformin is available in the following forms:

• Tablets: A person usually takes these two or three times per day with meals.
• Extended-release tablets: These are long lasting, and a person usually takes one pill with their evening meal.
• Liquid: A person typically takes this once or twice per day with meals.

RECALL OF METFORMIN EXTENDED RELEASE

In May 2020, the Food and Drug Administration (FDA) recommended that some makers of metformin ER (extended-release) remove some of their tablets from the U.S. market. This is because an unacceptable level of a probable carcinogen (cancer-causing agent) was found in some extended-release metformin tablets. If you currently take this drug, call the clinician who prescribed it. They will advise you on whether you can continue to take the medication or you need a new prescription.

Initially, a doctor usually recommends a low dose of metformin. Depending on how the individual’s blood sugar levels respond to the medication, the doctor may gradually increase the dose.

In more severe cases, the doctor may prescribe a combination of metformin and other diabetes medications, which may include insulin.

Some medications are combinations of metformin and another antidiabetic medication, such as:

• Kombiglyze: metformin and saxagliptin
• Jentadueto: metformin and linagliptin

When taking metformin or any other medication, a person should carefully follow their doctor’s or pharmacist’s instructions.

Although it is generally safe to drink alcohol in moderation when taking metformin, drinking too much can increase the risk of serious side effects such as hypoglycemia and lactic acidosis, which is a potentially life threatening condition.

Hypoglycemia, or low blood sugar, can cause symptoms such as:

• confusion
• dizziness
• tiredness
• hunger
• nervousness

Severe hypoglycemia is dangerous and requires immediate medical attention.

Common side effects of metformin include:

• nausea
• vomiting
• diarrhea
• abdominal pain
• loss of appetite
• flatulence
• rash
• metallic taste in the mouth
• headache
• runny nose
• muscle soreness

If a person experiences severe side effects, they may need to stop taking metformin temporarily.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors

SGLT2 inhibitors are a relatively new group of oral medications for type 2 diabetes.

They work by increasing the amount of sugar the kidneys absorb from the bloodstream and pass out through the urine. This helps lower a person’s blood sugar levels.

Doctors usually prescribe SGLT2 inhibitors in combination with metformin when metformin alone cannot sufficiently lower blood sugar levels. However, a doctor may prescribe an SGLT2 inhibitor alone, especially if a person cannot take metformin.

A person typically takes an SGLT2 inhibitor once per day. Drugs in this category include:

• canagliflozin (Invokana)
• dapagliflozin (Forxiga)
• empagliflozin (Jardiance)

Because of their effect on the kidneys, SGLT2 inhibitors increase a person’s risk of contracting genital and urinary tract infections. Doctors do not recommend these drugs for people with kidney diseases.

Dipeptidyl peptidase-4 (DPP-4) inhibitors

DPP-4 inhibitors, or gliptins, are a newer class of oral drugs for type 2 diabetes.

They increase insulin production in the body and decrease the amount of sugar the liver releases into the bloodstream. These effects help lower a person’s blood sugar levels.

Doctors usually prescribe DPP-4 inhibitors in combination with metformin when metformin alone cannot lower blood sugar levels enough. In certain circumstances, a doctor may prescribe a DPP-4 inhibitor alone as a first-line treatment for type 2 diabetes.

A doctor may be more likely to prescribe these drugs to people who:

• have chronic kidney disease
• are older
• are of African American descent

A person typically takes a DPP-4 inhibitor once daily. Available drugs in this class include:

• alogliptin (Nesina)
• linagliptin (Tradjenta)
• saxagliptin (Onglyza)
• sitagliptin (Januvia)

Alpha-glucosidase inhibitors (AGIs)

AGIs work by slowing digestion and reducing the absorption of sugar into the bloodstream. A person usually takes an AGI three times per day with the first bite of each meal.

Available AGIs include acarbose (Glucobay and Precose) and miglitol (Glyset). Doctors usually prescribe them in combination with other diabetes medications, such as metformin.

Side effects of AGIs can include diarrhea, stomach upset, and gas.

Insulin secretagogues

These oral medications cause the pancreas to produce more insulin, which helps regulate blood sugar levels.

There are two main types of insulin secretagogues:

• sulfonylureas, such as:
  • glimepiride
  • glipizide
  • glyburide
  • chlorpropamide
  • tolbutamide
  • tolazamide
• meglitinides, such as:
  • repaglinide
  • nateglinide

A person usually takes sulfonylureas once or twice per day and meglitinides 2–4 times per day with meals.

Doctors usually prescribe insulin secretagogues in combination with other diabetes medications, such as metformin. These drugs may increase a person’s risk of hypoglycemia and cause slight weight gain.

Thiazolidinediones (TZDs)

TZDs are sometimes called glitazones. They increase the body’s sensitivity to insulin, which allows the hormone to regulate blood sugar levels more effectively.

Doctors usually prescribe TZDs only if other first-line treatments, such as metformin, have not had the desired effect.

TZDs are oral tablets, and a person usually takes them once or twice per day, with or without food. It is important to take these medications at the same time each day.

Pioglitazone (Actos) is an example of a TZD. Some medications include a combination of a TZD and another diabetes drug, such as one in the sulfonylurea class or metformin.

Side effects of TZDs can include:

• body fluid retention, which can lead to swelling
• weight gain
• vision difficulties
• skin reactions
• respiratory infections

In recent years, doctors have been less likely to prescribe TZDs because of concerns that they may increase the risks of heart failure and bladder cancer.

In addition to insulin, many other medications for type 2 diabetes are available in injectable form, including glucagon-like peptide-1 (GLP-1) agonists.

GLP-1 agonists

GLP-1 agonists, sometimes called incretin mimetics, work by increasing the body’s production of insulin and reducing the amount of sugar the liver releases into the bloodstream.

These effects help:

• lower blood sugar levels
• reduce appetite
• promote weight loss, in combination with dietary changes and exercise

Doctors often prescribe GLP-1 agonists in combination with metformin when metformin alone does not sufficiently regulate blood sugar levels.

If a person cannot take metformin, a GLP-1 agonist is often the next choice. These drugs are self-injectable, and several types are available.

The frequency of injections depends on the drug. For example:

• Liraglutide (Victoza) is a once-daily injection.
• Exenatide (Byetta) is a twice-daily injection.
• Exenatide extended-release pen (Bydureon) is a once-weekly injection.
• Dulaglutide (Trulicity) is a once-weekly injection.
• Semaglutide (Ozempic) is a once-weekly injection.
• Tirzepatide (Mounjaro) is a once-weekly injection that acts on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP).

A person may experience stomach upset and nausea when they begin to use a GLP-1 agonist, but this usually passes. The drugs have a low risk of causing hypoglycemia.

Common side effects of GLP-1 agonists include:

• nausea
• diarrhea
• vomiting
• headaches
• stomach upset
• loss of appetite

Amylin analogs

Amylin analogs, or amylin agonists, work by slowing digestion and reducing the amount of sugar the liver releases into the bloodstream. This helps prevent blood sugar levels from rising too much after eating.

Amylin analogs also make people feel full longer, which can contribute to weight loss.

A person needs to inject an amylin analog before meals. The only type available in the U.S. is pramlintide (Symlin). Doctors usually prescribe it alongside insulin treatment.

Some people experience nausea and vomiting when they begin taking this type of drug, but these side effects generally improve over time.

According to guidelines published in 2018, the American College of Cardiology recommends prescribing GLP-1 receptor agonists or SGLT2 inhibitors if a person has a diagnosis of:

• cardiovascular disease due to atherosclerosis
• chronic kidney disease

The guidelines recommend SGLT2 inhibitors specifically for people with heart failure or a risk of heart failure due to atherosclerotic cardiovascular disease.

Lifestyle and dietary changes are a crucial part of any treatment plan for type 2 diabetes. Some people can manage the condition with these changes alone.

Lifestyle tips for managing type 2 diabetes include:

• maintaining a moderate body weight, or losing weight if a doctor recommends it
• monitoring blood sugar levels regularly, as directed by a doctor
• eating a nutrient-dense diet
• getting at least 7 hours of sleep each night
• getting at least 150 minutes of moderate-intensity exercise each week through activities such as walking briskly, mowing the lawn, swimming, cycling, or playing sports
• moderating cholesterol and blood pressure levels
• refraining from smoking

Dietary tips for managing type 2 diabetes include:

• eating fiber-rich foods, such as whole grains, nuts, leafy greens, and legumes
• eating lean meats and proteins, such as fish, poultry, and legumes
• avoiding highly processed foods
• avoiding sugary foods and drinks
• reducing the intake of alcohol
• eating smaller portions
• avoiding fast food and fried foods
• checking the nutritional content of food items

A doctor or dietitian can give personalized advice about an individual’s diet and exercise regimen. They can also provide ongoing support and monitoring.

People should follow a doctor’s instructions closely when taking diabetes medications.