How it works: Combination therapy for type 2 diabetes

Combination therapy is a treatment that uses two or more medications to address various health conditions, such as type 2 diabetes.

Type 2 diabetes is a chronic disease that occurs when blood sugar levels rise as a result of problems with the use or production of insulin in the body. Over time, untreated high blood glucose levels can lead to complications such as heart or kidney disease.

Along with lifestyle changes, metformin is the first line of treatment for type 2 diabetes. This oral medication improves the body’s response to insulin, which helps lower blood glucose. People who do not tolerate metformin well may take another type of diabetes medication.

However, one medicine alone is not always enough to keep blood glucose levels within target range. For people with type 2 diabetes, it is often harder to manage blood glucose levels over time. That is why combination therapy may prove more effective.

Doctors may prescribe combination therapy to people with type 2 diabetes who have high blood glucose levels despite relying on treatment with metformin or another medication.

“Metformin is still the usual first line of treatment,” Dr. Barbara Keber, the chair of family medicine at Glen Cove Hospital on Long Island, NY, told Medical News Today.“ Additional medications are utilized when that therapy alone does not control glucose levels adequately.”

People with type 2 diabetes who are at higher risk of experiencing diabetes-related complications will receive combination therapy even if their blood glucose levels are within target range. This includes people with:

• coronary artery disease or high risk of developing it
• chronic kidney disease
• heart failure

The American Diabetes Association (ADA) recommends combination therapy with a glucagon-like-peptide-1 receptor agonist (GLP-1 RA) or sodium-glucose transport protein 2 (SGLT2) inhibitor for people with these conditions.

A doctor may prescribe both of these medications together.

Combination therapy usually uses metformin with one or more of the following medications:

GLP-1 RAs or DPP-4 inhibitors

The liver produces, stores, and releases glucose into the bloodstream based on the instructions that insulin sends. This means the liver plays an essential role in regulating and stabilizing the body’s blood glucose levels.

GLP-1 RAs are incretins. After a person ingests food, incretins increase insulin release from the pancreas and decrease glucagon. This lowers the levels of glucose released from the liver.

Dipeptidyl-peptidase-4 (DPP-4) inhibitors are medications that block DPP-4. DPP-4 is an enzyme destroys GLP-1 incretins, which are hormones that help control the release of insulin.

GLP-1 RAs and DPP-4 inhibitors:

• decrease appetite
• promote a feeling of fullness
• support efficient insulin production
• reduce the amount of glucose that the liver releases

A Cochrane review of studies reports that GLP-1 RAs are among the most effective medications for lowering blood glucose levels. Studies also link most types of GLP-1 RAs to weight loss.

DPP-4 inhibitors tend to be less effective at reducing levels of blood glucose. They may or may not contribute to some weight loss.

“DPP-4 inhibitors are useful in some patients but do not add to the reduction in the A1C as much as the GLP-1 RA or SGLT2 inhibitors,” said Dr. Keber. “They should not be used in conjunction with GLP-1 RA, as they work in the same pathway,” she added.

A1C is a measure of your average blood glucose levels over the past three months.

SGLT2 inhibitors

One of the functions of the kidneys is to filter the blood. They also remove waste and excess water to make urine.

By blocking the SGLT protein, SGLT2 inhibitors stop the kidneys from reabsorbing glucose into the bloodstream. Instead, glucose is released in the urine. This helps lower blood sugar levels.

“Glucose is allowed to be removed from the blood at a higher rate than would normally be the case,” explained Dr. Minisha Sood, an endocrinologist at Lenox Hill Hospital in New York, NY.

The Cochrane review found that SGLT2 inhibitors tend to have a smaller effect on blood glucose levels than GLP-1 RAs. However, studies have more consistently linked SGLT2 inhibitors to weight loss.

Other medications

Combination therapy may include other medications:

• Thiazolidinediones (TZDs): These drugs make the body more sensitive to insulin, which helps lower blood sugar levels. They also reduce the amount of glucose that the liver releases into the bloodstream.
• Sulfonylureas (SUs): This group of medication helps the pancreas produce and release insulin.
• Basal insulin: This medicine supplements the insulin that the body produces on its own.

“Sometimes, insulin is needed in addition to metformin or other agents when the blood sugars are very high,” Dr. Keber said.

The ADA recommends insulin when a person with type 2 diabetes:

• has A1C levels greater than 10% or blood glucose levels 300 milligrams per deciliter or higher
• has symptoms of hyperglycemia, or high blood glucose
• experiences unexplained weight loss

Sometimes, doctors may prescribe insulin to bring glucose levels down before they gradually reduce the prescribed dose and remove insulin from a person’s treatment plan.

In other cases, a person may need to take insulin on an ongoing basis.

Combination therapy can help lower blood sugar levels and keep them within target range. This in turn lowers the risk of diabetes-related complications.

GLP-1 RAs and SGLT2 inhibitors offer additional benefits.

GLP-1 RAs may help:

• support weight loss
• reduce blood pressure
• prevent coronary artery disease
• stop coronary artery disease from worsening

SGLT2 inhibitors may help:

• facilitate weight loss
• reduce blood pressure
• prevent kidney damage from diabetes
• stop heart failure from becoming worse

The ADA reports that GLP-1 RAs and SGLT2 inhibitors may also reduce the risk of death from cardiovascular causes, including heart attack and stroke.

Some medications may not be safe for people with certain health conditions. For example, people with medullary thyroid cancer should not take GLP-1 RAs or DPP-4 inhibitors.

Moreover, people with heart failure or liver disease should not take TZDs.

Each medication for type 2 diabetes carries some risk of side effects. Common side effects include:

• Hypoglycemia: Any medication that lowers blood sugar levels may cause them to drop below what doctors consider safe. Also, insulin and SUs carry higher risk of hypoglycemia than other diabetes medications.
• Weight gain: TZDs, SUs, and insulin may cause weight gain.

People with diabetes should always consult a healthcare professional about the potential benefits and risks of any medication before taking it.

When doctors decide which type of combination therapy will be most suitable for a person, they consider the following:

• whether the person has coronary artery disease, chronic kidney disease, or heart failure
• whether they have a history of hypoglycemia
• how the treatment will affect their weight
• the risk of side effects from treatment
• the person’s treatment priorities and goals
• the treatment cost

A person should always seek guidance from a doctor if they do not understand why they are receiving a specific therapy or if they have any other questions about their treatment plan.

Combination therapy can help maintain blood glucose levels within target range. This reduces a person’s risk of experiencing complications from type 2 diabetes.

Some types of combination therapy also offer benefits for weight loss, heart health, or kidney health.

A healthcare professional can explain the potential risks and benefits of different types of combination therapy.