Drug Combinations for Type 2 Diabetes

As diabetes progresses over time, many people with type 2 end up needing to take multiple medications. So, it can be convenient to have them combined in one pill.

A potential drawback of using a combination medication is that it’s harder to adjust the dosage; the medications come with certain doses of one medication in ratio to the other.

Let's look at the different combination products used to treat type 2 diabetes, who should take them, and pros and cons. Your health care professional will help you find the best drug combination for your type 2 diabetes.

How Does Metformin Work for Type 2 Diabetes?

For most people with type 2 diabetes, metformin is the first medication started after diagnosis. Metformin is the only medication classified as a biguanide. It works by reducing how much glucose your liver makes, lowering the amount of glucose absorbed from your GI tract, and improving your cells’ response to insulin (i.e. insulin sensitivity).

When metformin isn’t enough to control your blood sugar levels, your health care provider may add another medication to your regimen.

Combination Medications Used to Treat Type 2 Diabetes

Combination medications are two or more medicines put into one tablet or injection. These combinations help control your diabetes better than either medication on its own.

Here are the combination medications currently available in the U.S.:

Biguanides/DPP-4 Inhibitors

• metformin/alogliptin (Kazano)

• metformin/linagliptin (Jentadueto, Jentadueto XR)

• metformin/saxagliptin (Kombiglyze XR)

• metformin/sitagliptin (Janumet)

Biguanides/DPP-4 Inhibitors/SGLT-2 Inhibitors

• metformin/linagliptin/empagliflozin (Trijardy XR)

• metformin/saxagliptin/dapagliflozin (Qternmet XR)

Biguanides/Meglitinides

• metformin/repaglinide (PrandiMet)

Biguanides/SGLT-2 Inhibitors

• metformin/canagliflozin (Invokamet)

• metformin/dapagliflozin (Xigduo XR)

• metformin/empagliflozin (Synjardy)

• metformin/ertugliflozin (Segluromet)

Biguanides/Sulfonylureas

• metformin/glipizide

• metformin/glyburide

Biguanides/Thiazolidinediones

• metformin/pioglitazone (Actoplus Met, Actoplus Met XR)

• metformin/rosiglitazone (Avandamet)

DPP-4/SGLT-2 Inhibitors

• linagliptin/empagliflozin (Glyxambi)

• sitagliptin/ertugliflozin (Steglujan)

• saxagliptin/dapagliflozin (Qtern)

DPP-4 inhibitors/Sulfonylureas

• alogliptin/pioglitazone (Oseni)

GLP-1 Receptor Blocker/Insulin

• lixisenatide/insulin glargine (Soliqua)

• liraglutide/degludec insulin (Xultophy)

Sulfonylureas/Thiazolidinediones

• glimepiride/pioglitazone (Duetact)

• glimepiride/Rosiglitazone (Avandaryl)

Drug class: Biguanides (Metformin)

• How they work: Reduce how much glucose your liver makes, lower the amount of glucose absorbed from your GI tract, improve cells’ response to insulin

• Side effects: GI-related distress (diarrhea, nausea, vomiting), lactic acid build-up (lactic acidosis), vitamin B12 deficiency

• Who shouldn’t take them: Those with severe kidney or liver impairment

• Pros (for some): Weight loss

• Cons: Dose needs to be adjusted in those with kidney impairment and held before and after receiving iodinated contrast dye for imaging studies

Drug class: Dipeptidyl peptidase-4 (DPP-4) inhibitors

• How they work: Improve insulin secretion and decrease glucagon secretion

• Side effects: Severe joint pain (rare), fluid-filled blisters (bullous pemphigoid)

• Who shouldn’t take them: Those with a history of pancreatitis

• Pros: Improve blood pressure and decrease glucose levels after meals

• Cons: Must use caution in those with heart failure or who are breastfeeding

Drug class: Meglitinides

• How they work: Increase insulin secretion when glucose is present in the blood

• Side effects: Hypoglycemia, weight gain

• Who shouldn’t take them: Those taking a medication called gemfibrozil or insulin NPH, or who have liver problems

• Cons: Frequent dosing—taken three times a day with meals

Drug class: Sodium-glucose cotransporter 2 (SGLT 2) inhibitor

• How they work: Prevents the kidneys from reabsorbing glucose, increasing the elimination of glucose through the urine

• Side effects: Genital yeast and urinary tract infections, dehydration, fractures, diabetic ketoacidosis (rare)

• Who shouldn’t take them: Those in their second or third trimester of pregnancy or who are breastfeeding; those on dialysis

• Pros: Causes weight loss, decreases blood pressure, and improves heart failure symptoms

• Cons: Requires dose adjustment for kidney function, may need to hold doses if acutely ill or dehydrated

Drug class: Sulfonylurea

• How they work: Increase insulin secretion from the pancreas

• Side effects: Hypoglycemia (low blood sugar), weight gain

• Cons: Those with kidney or liver impairment may need lower doses; use caution in those with sulfa allergy

Drug class: Thiazolidinediones

• How they work: Increase insulin sensitivity

• Side effects: Edema (swelling), weight gain

• Who shouldn’t take them: Those with heart failure or bladder cancer

• Pros: No dose adjustments needed, can decrease triglyceride levels

• Cons: Increases the risk of osteoporosis

Drug class: Glucagon-like protein-1 (GLP-1) receptor antagonist

• How they work: Increase insulin secretion when glucose is present and prevent glucagon secretion

• Side effects: GI-related such as nausea and vomiting

• Who shouldn’t take them: Those with a history of pancreatitis, thyroid cancer, or who are pregnant or breastfeeding

• Pros: Weight loss, improves heart health

• Cons: Requires an injection; those with severe kidney impairment may need lower doses

Studies for Medication Combinations

When added to metformin, non-insulin medications may lower your hemoglobin A1c (HbA1c) by an additional 0.7% to 1%. HbA1c is a measure of your average blood sugar levels over the three months prior to the test. The HbA1c helps your health care provider know how well controlled your diabetes is.

A 2016 study reported that metformin plus GLP-1 receptor agonists were more effective at lowering HbA1c than other metformin combinations. But it was also associated with the most GI side effects. Metformin plus GLP-1 or SGLT-2 inhibitors also significantly reduced blood pressure more than metformin alone.

Along the same lines, a 2018 study found no significant difference in HbA1c lowering between dapagliflozin (SGLT-2 inhibitor) plus metformin or glimepiride (sulfonylurea) plus metformin. But, dapagliflozin plus metformin caused a greater reduction in fasting blood glucose levels. Triple therapy with dapagliflozin, saxagliptin (DPP-4 inhibitor), and metformin was far better at controlling HbA1c than dual therapy of glimepiride plus metformin.

Sulfonylureas, like glimepiride, increase the risk of hypoglycemia when used alone or in combination with other non-insulin medications.

A small 2022 study showed that metformin plus linagliptin (DPP-4 inhibitor) significantly reduced HbA1c compared to metformin plus a SGLT-2 inhibitor or metformin alone. In addition, triple therapy with linagliptin, metformin, and empagliflozin (SGLT-2 inhibitor) showed better glycemic control than dual therapy with metformin and linagliptin.

The combination of SGLT-2 with DPP-4 inhibitors showed greater improvements in HbA1c compared to DPP-4 inhibitors alone, according to one 2018 study. This combination also promotes weight loss without increasing the risk of hypoglycemia or urinary tract infections.

Each medication combination has its risks and benefits. Based on your medical history, some combinations may be better for you than others. Because of this, treatment plans for type 2 diabetes are individualized to help you meet your treatment goals.