Metformin Not Enough? GLP-1 & SGLT2 Add-On Options for Diabetes

Type 2 diabetes affects more than 35 million adults in America and occurs when your body can no longer effectively regulate blood sugar (glucose). When blood sugar rises, the pancreas normally releases insulin to help move glucose out of the blood and into cells. With type 2 diabetes, though, the cells become less responsive to insulin, leading to health complications from persistently elevated blood sugar.

Metformin is commonly prescribed to lower blood sugar in people with type 2 diabetes. However, it is far from the only option available. In fact, other medications like GLP-1s receptor agonists and SGLT2 inhibitors may be prescribed instead of or alongside metformin to help control blood sugar levels in people with type 2 diabetes. Choosing the right treatment depends on factors like your blood sugar levels, your overall health, and the risk of different side effects.

Common Non-Insulin Diabetes Medications

Metformin IR/ER

Metformin works by causing your liver to produce less glucose. It can also make it easier for your body to respond to insulin, which helps move glucose out of your blood. 

Metformin comes in both immediate release (IR) and extended release (ER) formulations. While these medications have the same active ingredient, they are not interchangeable. The pills release metformin into the blood at different rates. As a result, you often take metformin IR twice per day, while metformin ER is generally taken once daily. 

Metformin can cause gastrointestinal problems like diarrhea, but the ER formulation has fewer gastrointestinal side effects. Taking metformin according to your prescribed schedule and with food helps the medication work as intended. Talk to your doctor before making any adjustments to the type, timing, or dosage of metformin.

How To Tell When Metformin IR Isn’t Enough

If you have type 2 diabetes, your doctor will work with you to set a target range for your blood sugar levels. Then you’ll have blood tests at least twice per year (and potentially more often) to see if your diabetes is under control.

For example, an A1C test reflects your blood sugar levels over the last three months. If your A1C is higher than your goal, it may mean that your current treatment is not enough to keep your blood sugar within your target range. Your doctor may suggest that you take another drug with metformin or switch to a new diabetes medication.

Can Metformin ER Help?

Metformin ER is not a different drug or a stronger medication than metformin IR. But metformin IR and ER are released differently in the body, which changes their dosing schedules. 

If you get an upset stomach or diarrhea from metformin IR, one option is to try taking metformin ER instead. Because the medication is released into the body more slowly over the course of the day, you may experience fewer gastrointestinal problems with metformin ER. In addition, once-daily dosing may be more convenient if you have trouble remembering to take your pills twice a day. 

Because metformin IR and ER aren’t directly interchangeable, you should talk with your doctor about your prescription, when you should take it, and what you can do to address any side effects you experience.

GLP-1 Receptor Agonists

GLP-1 receptor agonists mimic the effects of GLP-1, a hormone naturally made in the gut. These drugs help treat diabetes in multiple ways, including by spurring the pancreas to release insulin when blood sugar is elevated. They slow digestion and help you feel fuller for longer. GLP-1 receptor agonists also reduce the release of glucagon, a hormone that raises blood sugar.

However, due to its impact on slowing digestion, possible side effects of GLP-1s include gastrointestinal issues like nausea, vomiting, diarrhea, and constipation. For some, these side effects lessen as they adjust to the medication.

GLP-1 receptor agonists can help manage diabetes, and some have also been shown to reduce the risk of major cardiovascular complications. Many of these drugs also promote weight loss, though not all are FDA-approved for the same things. For example, Ozempic is only FDA-approved for managing type 2 diabetes, while Wegovy and Zepbound are FDA-approved for weight loss.

One specific drug, called tirzepatide (Mounjaro), is a dual-receptor agonist, which means it mimics both GLP-1 and another hormone called GIP. It is approved to help manage blood sugar in people with type 2 diabetes.

A GLP-1 or dual GIP/GLP-1 receptor agonist can be taken with or without metformin. Most GLP-1 drugs are self-administered injections, but semaglutide (another form of GLP-1 drug) is also available in an oral formulation (Rybelsus). 

SGLT2 Inhibitors

As blood passes through your kidneys, glucose is filtered out of the blood. Your kidneys normally reabsorb most of that glucose and return it to the bloodstream. 

A protein called sodium-glucose cotransporter 2 (SGLT2) facilitates that reabsorption. SGLT2 inhibitors are prescription medications that block this protein so that more glucose is removed from the body through your urine instead of going back into the blood.

In addition to helping control blood sugar, SGLT2 inhibitors may reduce the risk of cardiovascular complications and kidney disease in people with diabetes. They can also promote modest weight loss. Like GLP-1 receptor agonists, SGLT2 inhibitors may be prescribed with or without metformin.

Because SGLT2 inhibitors impact your kidneys and urination, side effects may include more frequent urination, vaginal yeast infection, and urinary tract infections. Patients should also be wary of other risks that could arise from frequent urination, including dehydration, dizziness, and low blood pressure.

DPP-4 Inhibitors

DPP-4 inhibitors are medications that help prevent the breakdown of the GLP-1 and GIP hormones made in the gut. When you take a DPP-4 inhibitor, these hormones stay active for longer, helping increase insulin release and reduce glucagon when your blood sugar level is elevated.

DPP-4 inhibitors tend to have a smaller effect on blood sugar than GLP-1 receptor agonists and SGLT2 inhibitors. They also have not demonstrated the same cardiovascular or kidney benefits as certain GLP-1 receptor agonists and SGLT2 inhibitors.

Sulfonylureas

Sulfonylureas stimulate cells in the pancreas to release more insulin. They are usually taken with or shortly before a meal, depending on the specific medication. Because sulfonylureas increase insulin release regardless of whether your blood sugar levels are high, they can cause your blood sugar to drop too low (hypoglycemia), especially if you delay or skip a meal. These drugs can also cause weight gain.

Thiazolidinediones

Thiazolidinediones (TZDs) are drugs that make your body more sensitive to insulin. TZDs can also decrease the amount of glucose made by your liver. TZDs can cause swelling in your legs and feet from fluid retention, as well as cause weight gain. They can also increase the risk of heart failure or worsen heart failure in some people.

Combination Medications

Some medications have two active ingredients in a single tablet. For example, Jentadueto is a combination of metformin and a DPP-4 inhibitor (linagliptin), and Xigduo XR combines metformin with an SGLT2 inhibitor (dapagliflozin). 

If you need both active ingredients, a combination tablet can reduce the number of pills you have to take and simplify your treatment schedule.

When To Add a Second Diabetes Medication

Your doctor may recommend adding another medication if your current treatment isn’t keeping your blood sugar within your target range. Even if your blood sugar is at goal, they may recommend certain medications for other reasons, like weight loss or heart or kidney benefits.

When deciding whether another medication is appropriate, your doctor considers multiple factors, including: 

• Your recent blood tests and how your blood sugar levels compare to your target range
• Your current dose of metformin
• Your age, weight, and overall health
• Whether you have or are at risk for heart disease, heart failure, kidney disease, or other diabetes-related complications
• Other medications or supplements you take and potential drug interactions
• Your risk of low blood sugar (hypoglycemia)
• How well you tolerate metformin and the potential side effects of other medications
• Your preferences for dosing schedules and administration (including oral vs. injectable formulations)
• Your expected out-of-pocket costs for different medications

As this list demonstrates, there’s no single thing that doctors look at to decide whether to adjust your diabetes treatment. That’s why working closely with your healthcare provider is essential to finding a treatment plan that offers you the most benefits with the fewest downsides.

GLP-1 vs. SGLT2: How Doctors Decide

Doctors can choose among many different drugs for diabetes, but GLP-1 receptor agonists and SGLT2 inhibitors are commonly prescribed because they can lower blood sugar while offering additional benefits, such as weight loss. 

Both GLP-1 receptor agonists and SGLT2 inhibitors can help keep blood glucose within your target range. Certain drugs in both classes can contribute to cardiovascular or kidney health, although their specific benefits can differ.

On their own, these two classes of drugs have a relatively low risk of causing hypoglycemia. That said, the risk may increase if you’re also taking other diabetes medications like sulfonylureas.

GLP-1 receptor agonists tend to have a greater impact than SGLT2 inhibitors on weight loss. They may also be recommended if you have diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), especially if you also have obesity or are at an increased risk of liver fibrosis. However, these drugs can cause gastrointestinal problems, such as nausea and diarrhea. Most require regular self-injections, which some people may prefer to avoid. 

SGLT2 inhibitors may be favored when heart failure or chronic kidney disease is an important treatment consideration. A downside of these drugs is a heightened risk of genital yeast infections that occurs because SGLT2 inhibitors increase the amount of glucose in your urine. 

Ultimately, these are not simple decisions. They require analyzing your health, treatment goals, potential side effects, cost, and personal preferences. Ask your healthcare provider about the pros and cons of GLP-1 receptor agonists, SGLT2 inhibitors, and other diabetes medications before settling on a treatment plan.

What To Ask Before Changing Diabetes Medication

Talking about diabetes treatment with your healthcare provider may feel overwhelming. Preparing a list of questions beforehand and taking notes at your appointment can help you compare the pros and cons of different options.

Some questions you may want to ask your healthcare provider before changing diabetes medications include:

• Is my blood sugar target still the same? 
• Which drug or drugs are most likely to help me reach my target?
• Do these medications interact with any other medications or supplements that I take?
• Do I have any health issues that would make one of these medications unsafe or less appropriate for me?
• Should I keep taking metformin with the new medication?
• What are the most common side effects of each option and how can I minimize them?
• What should I do if I have severe side effects?
• How do I use the medication? How often do I need to take it?
• Will this medication affect my weight?
• Will my insurance cover this medication? How much will I have to pay?
• How soon will we check to see if this treatment is working?
• How do I safely stop or change my medication regimen if absolutely necessary?

Your Next Steps

Diabetes treatment may change over time. If your blood sugar is no longer in your target range or if other medications could provide additional health benefits, your doctor may suggest changing your treatment plan. 

Many drugs are available that can be used in combination with or instead of metformin. Because diverse factors go into choosing diabetes medications, you should talk with your doctor about your goals and treatment options before making any changes.