What Are My Choices for Metformin Alternatives?
By Andrew Briskin
While you are likely familiar with metformin and insulin as the two well-known medications for treating type 2 diabetes, many other options are available to help you manage your glucose levels. Here is a rundown of some of the other options that may improve your health and diabetes management.
When you are diagnosed with type 2 diabetes, you will likely hear from your healthcare team that the most common initial treatment regimen consists of some combination of metformin and lifestyle changes to your diet and exercise.
For most people, type 2 diabetes is a progressive disease (this means that without proper treatment it can continue to worsen over time). In addition, some people may have more severe and chronic hyperglycemia for a long time prior to being diagnosed with type 2 diabetes. As a result, you might need additional medications the longer you have diabetes to keep your glucose levels in a healthy range.
Insulin remains the most effective therapy to lower glucose, particularly in comparison to most oral medicines for type 2 (including metformin). Therefore, at the time of diagnosis, if there is evidence of long-standing and persistent hyperglycemia, you may be advised to start insulin, since it is most effective and rapid in its action to lower glucose levels. Once diagnosed, if you are unable to meet your glucose targets (whether that be because your condition has progressed over time, your current medications are not doing enough to lower your glucose, or because you were experiencing significant symptoms), your healthcare team may suggest using insulin.
While these treatments are some of the most well-known, there are many other medications available today for people with type 2. These additional drugs have dramatic effects; many of them can lower your risk for various diabetes-related complications, while still maintaining similar glucose-lowering properties.
"People with diabetes should be aware of their need for different medications based on their risk profiles," said Dr. Robert Gabbay, chief scientific and medical officer for the American Diabetes Association. "All people with diabetes should also be referred for and receive DSMES, or diabetes self-management education and support, at diagnosis. This gives people the opportunity to engage with a skilled diabetes care and education specialist, ask questions about therapies, and increase awareness."
As new diabetes drugs continue to receive FDA approval at an unprecedented rate, here is a look at the different types of medications that can improve your health and help you better manage your diabetes. If you are at an increased risk for developing complications, or your glucose levels have not responded well with metformin, talk with your healthcare provider about whether these medications may be a better option.
SGLT-2 inhibitors
SGLT-2 inhibitors are oral medications that can help lower your glucose levels by helping your body remove excess glucose by excreting it in your urine. These drugs can lower A1C levels, and research has shown that they can also slow the progression of kidney disease and protect against heart disease (heart attack, stroke, hospitalization for heart disease and death) and heart failure. However, SGLT-2 inhibitors should not be prescribed to those who have already progressed to stage 4 or end stage kidney disease.
Additionally, unlike other glucose-lowering drugs, SGLT-2s come with a relatively low risk of hypoglycemia. The currently available SGLT-2 inhibitors include Farxiga, Invokana, Jardiance, and Steglatro.
Side effects of taking an SGLT-2 inhibitor may include:
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More frequent urination
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Increased risk for urinary tract infections and genital yeast infections
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Increased risk for kidney damage for those already at advanced stages of kidney disease
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Increased risk for diabetic ketoacidosis (DKA)
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Low blood pressure, syncope (loss of consciousness caused by low blood pressure), and dehydration due to volume depletion
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Invokana, specifically, may increase your risk for amputations, ketoacidosis, and kidney damage beyond that associated with other SGLT-2 drugs.
GLP-1 receptor agonists
GLP-1 receptor agonists are another type of glucose-lowering medication, which can either be taken orally or, more commonly, through a once-daily or once-weekly injection. GLP-1 receptor agonists can lower your A1C levels, and some have been shown to lower your risk for heart and kidney disease as well.
Perhaps most remarkable, however, is that taking a GLP-1 receptor agonist can lead to significant weight loss. If you have struggled with weight management through diet and exercise changes alone, talk with your healthcare provider about starting a GLP-1 receptor agonist. The currently available medications in this class are Adlyxin, Bydureon, Byetta, Ozempic, Rybelsus, Trulicity, and Victoza.
Side effects of taking a GLP-1 receptor agonist may include:
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Nausea
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Vomiting and diarrhea (usually decreases over time)
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Risk for hypoglycemia, if taken in combination with insulin or a sulfonylurea (read below)
DPP-4 inhibitors
DPP-4 inhibitors are a class of drugs that can lower your glucose by inhibiting glucagon release in your body, a hormone that causes your blood sugar to rise. This helps stimulate insulin production and decreases the emptying of your stomach, making you feel more full. Both of these effects help lower glucose levels. These drugs are taken orally and are often combined with metformin to bolster the glucose-lowering action. When taken with metformin, there is a low risk for low blood sugar with a DPP-4 inhibitor, but taking them with insulin or sulfonylureas can place you at a higher risk.
While they can lower your glucose, DPP-4 inhibitors have not been shown to have the same effects on weight loss and complications as the SGLT-2 and GLP-1 drug classes. Available DPP-4 inhibitors include Januvia, Nesina, Onglyza, and Tradjenta.
Side effects include:
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Gastrointestinal problems
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Flu-like symptoms
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Increased risk for pancreatitis
Sulfonylureas (SFUs)
SFUs are a type of glucose-lowering medications that have been around for many years as a treatment for type 2 diabetes. While SFUs are effective at lowering glucose and are available as less expensive generic brands, they significantly increase your risk for low blood sugar and can cause weight gain. Given that other drug classes can lower your glucose and reduce complications without the added risk for hypoglycemia, you may want to discuss these other options with your healthcare provider.
Side effects include:
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Higher risk for experiencing hypoglycemia
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Weight gain
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Hunger
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Upset stomach
Thiazolidinediones (TZDs)
TZDs are another glucose lowering medication that work by reducing insulin resistance. Similar to SFUs, TZDs are cheaper and come in generic brands but can place users at a higher risk for negative side effects such as weight gain and an increased risk for heart failure. Discuss these risks with your healthcare provider to find the best option for you.
Side effects include:
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Weight gain
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Edema, or fluid buildup, usually in your feet, legs, hands, or arms
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Increased risk for heart failure or experiencing a bone fracture
Combination Drugs
Combination drugs, as the name suggests, combine two or more drugs, usually from different classes, into a single medication. Combination drugs can increase the effectiveness of each individual medication, reduce overall side effects, or decrease the total number of injections or pills in your daily treatment routine. Some currently available combination drugs include Janumet (Januvia + metformin), Kombiglyze XR (Onglyza + metformin extended release), and Synjardy (Jardiance + metformin).
Of course, these different drugs can also be taken as separate doses at the same time, or in combination with your insulin regimen. Layering multiple therapies can alleviate some negative side effects, help lower your glucose more effectively, and help prevent complications at the same time. Combination therapies allow your healthcare provider to develop a much more personal treatment for you.
Cost and access
Depending on your insurance coverage, drug costs are often a factor in determining which treatment you receive. Given how they minimize side effects and protect against complications, GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors are all ideal options, but they tend to be more expensive and aren’t yet available in generic forms in the US.
SFUs, TZDs, and metformin are available in generic brands and are typically much cheaper – but obviously, as is the case with SFUs and the risk of severe hypoglycemia, there may be reasons why these drugs are not preferred. Regardless, all of these medications can help you lower your glucose, so talk with your provider about which treatment fits your budget and insurance coverage.
For more about accessing affordable treatment options, read our article on How to Get Diabetes Drugs for Free.
The bottom line
While metformin and lifestyle modification remain the first-line therapies for type 2 diabetes, as you can see, there are several other medications that you may be able to try before needing to go on insulin. Depending on your risk for developing complications like heart or kidney disease, it’s often more effective to start using a GLP-1 receptor agonist or an SGLT-2 inhibitor before progressing to insulin injections.
This flowchart from the American Diabetes Association details the process for how your healthcare provider makes decisions on which medications may best for each individual. While the chart may seem complex, it illustrates the many different options that might be available to you depending on cost, risk factors, and overall health goals.
"Ask questions," said Dr. Gabbay. "Have a frank discussion with your diabetes care provider to understand the available options, why a treatment may or may not be for you, and ask questions to understand the treatments you do receive."
Talk with your healthcare provider about whether you might benefit from one of these drugs. The path from metformin to insulin is by no means direct, and there may be other options that can help you improve your diabetes management.
