Glipizide vs Metformin: What To Know

Oral diabetes medications are usually preferred by patients with diabetes compared to injectable medications like insulin and the newer non-insulin injectables (Ozempic, Trulicity, etc.)

Glipizide and metformin are two very commonly used (and affordable) oral diabetes medications, but they work in very different ways.

How do glipizide and metformin work – and can you take them together? In this article, we’ll answer those questions and more, along with comparing and contrasting glipizide vs metformin.

What is glipizide? 

Glipizide is the drug name for a medication used to treat type 2 diabetes. Common brand names for glipizide include Glucotrol and Glucotrol XL, which is an extended-release version of Glucotrol. 

You can also get a prescription for the generic versions, which are glipizide (or glipizide ER for extended release), which are less expensive.

Glipizide is in a drug class called sulfonylureas, which stimulates your pancreas to secrete more insulin. It was approved to treat type 2 diabetes in 2002 and isn’t meant to treat type 1 diabetes. Other common sulfonylureas include glyburide and glimepiride.

Dosages of glipizide usually start at 5 milligrams and can be increased to a maximum of 40 milligrams daily, either once daily or split among two doses 12 hours apart. 

You should try to take glipizide with meals to help reduce any stomach upset and to maximize effectiveness by reducing postprandial (after eating) blood sugar.

Compared to other types of sulfonylureas, glipizide comes with a lower risk of low blood sugar because it is absorbed quickly and has a shorter half-life (it remains in your system for less time). 

However, taking glipizide with other medications that can lower your blood sugar (such as insulin) can increase your hypoglycemia risk because glipizide increases your insulin secretion.

What is metformin? 

Metformin is the most commonly prescribed diabetes medication. The FDA approved metformin in 1994. 

Metformin is the generic name most commonly prescribed (less expensive), and the brand name for metformin is Glucophage.

Metformin is in a medication class called biguanides, which works by reducing the amount of sugar your liver makes while improving insulin sensitivity, helping to improve blood sugar levels. 

One of the benefits of metformin is that it doesn’t cause low blood sugar (hypoglycemia). Because it doesn’t cause low blood sugar, you can take metformin along with other medications like sulfonylureas (including glipizide) and injectable insulin.

The standard dosage of metformin ranges from 500 milligrams to a maximum of 2,550 milligrams per day. You should split the dose among meals, typically three times per day. 

There are two types of metformin – regular and extended-release (XR). If you experience side effects from regular metformin, your healthcare provider might suggest switching to the once-daily extended-release tablets to help reduce side effects.

Similarities and differences between glipizide and metformin

Similarities

• Oral medications approved to treat type 1 diabetes; neither are meant to treat type 1 diabetes, nor are they meant for people with DKA or HHS (very high blood sugar levels).
• Generally affordable options, especially when compared to newer diabetes medications that can cost hundreds to thousands of dollars per month without insurance.
• Meant to be taken with food to help reduce potential stomach discomfort.
• Can be used during pregnancy; however, glipizide should be discontinued a month before the expected delivery date to reduce the risk of low blood sugar in the infant. Metformin is considered safer during pregnancy (category B) compared to glipizide (category C).
• It can be used in breastfeeding, though glipizide should be the immediate-release version, not the extended-release, to help reduce potential low blood sugar in the baby.

Differences

• The method of action is different. Metformin helps reduce the amount of sugar your liver makes, and glipizide increases your pancreas’ secretion of the hormone insulin.
• Glipizide comes with a risk of low blood sugar, and metformin doesn’t.
• Glipizide can’t be combined with as many medications as metformin can due to the risk of low blood sugar.
• Metabolism: glipizide is primarily metabolized in your liver, while metformin isn’t metabolized and is primarily excreted in your kidneys/urine.
• Metformin is considered “weight neutral” (not likely to cause weight gain), while glipizide is associated with some weight gain.
• More frequent blood sugar monitoring may be required with glipizide compared to metformin due to the hypoglycemia risk.

• Metformin might need to be discontinued before having an X-ray with contrast done (especially if you have kidney disease with reduced kidney function), while you can take glipizide before that type of test.
• Time of approval: metformin was approved eight years sooner than glipizide.

Glipizide vs metformin effectiveness 

Glipizide

While there aren’t many studies on glipizide’s effectiveness on its own (it’s often combined with metformin), some sources cite a 1-2% reduction in A1c as typical for glipizide. 

However, according to a review on glipizide, it is unlikely to be effective on its own to reach blood sugar targets and is often combined with other medications like metformin to achieve blood sugar targets.

Glipizide increases insulin secretion, a hormone that can promote fat storage and can cause weight gain. This means you might be more likely to gain weight on glipizide vs on metformin. 

Metformin

Metformin can lower blood sugar levels in both obese and non-obese patients with type 2 diabetes. 

One study found that hemoglobin A1c levels dropped by a little over 1% in both obese and non-obese patients after 12 months of taking metformin.

At maximum doses, metformin might be able to lower your A1c by as much as 1.5%. Making healthy lifestyle changes in addition to taking metformin will help boost the effectiveness of metformin. 

According to a meta-analysis of 35 studies, each lasting at least 12 weeks, metformin tends to lower A1c levels by around 1%, whether alone or in conjunction with other diabetes medications.

If metformin alone isn’t helping you achieve your target blood sugar levels, your healthcare provider might suggest adding a new medication in addition to metformin.

The effectiveness of metformin tends to be dose-dependent, so it’s more likely to lower your blood sugar more significantly with higher doses.

Which has fewer side effects, glipizide or metformin?

Glipizide and metformin come with similar side effects. The main difference is that you might also experience low blood sugar with glipizide, so you could potentially experience more side effects with glipizide vs with metformin.

Glipizide side effects

Common side effects of glipizide include:

• Diarrhea
• Gas
• Feeling jittery
• Dizziness
• Uncontrollable shaking of a part of your body

Signs of a drug allergy to glipizide can include:

• Red or itchy skin
• Rash
• Hives
• Blisters

While rarer, you should watch out for these potentially serious side effects, which may indicate issues with your liver or other rare complications:

• Yellowing of your skin or eyes
• Light-colored stools
• Dark urine
• Pain in the upper right part of your stomach
• Unusual bruising or bleeding
• Fever
• Sore throat

If you experience low blood sugar from taking glipizide, you might experience symptoms including:

• Fast heartbeat
• Shaking
• Sweating
• Nervousness or anxiety
• Irritability or confusion
• Dizziness
• Hunger

To learn about glipizide interactions, we have a dedicated article for that.

Metformin side effects

The most commonly reported side effects from taking metformin are:

• Heartburn
• Stomach pain
• Nausea or vomiting
• Bloating
• Gas
• Diarrhea
• Constipation
• Weight loss
• Headache
• Metallic taste in your mouth

While rare, taking too much metformin can result in a dangerous condition called lactic acidosis, which can be fatal. 

There have been very few reports of lactic acidosis from metformin use, and many of the reports are from intentional overdoses. Taking metformin as prescribed comes with a very low risk of lactic acidosis.

Signs of lactic acidosis, which require immediate medical attention, might include:

• Abdominal or stomach discomfort
• Decreased appetite
• Diarrhea
• Fast, shallow breathing
• A general feeling of discomfort
• Muscle pain or cramping
• Unusual sleepiness, tiredness, or weakness

Which medication is cheaper?

According to GoodRx, a bottle of 60 tablets (500 milligrams each) of metformin costs around $4-$6 at most discount pharmacies (Walmart, Safeway, Walgreens, etc.) 

60 tablets (10 milligrams each) of glipizide will cost around $6 at the same types of pharmacies.

If you have healthcare insurance or prescription drug coverage, your cost for glipizide and metformin will likely be even lower.

Can I take glipizide and metformin together?

Glipizide and metformin are often taken together.

Your healthcare provider might suggest adding glipizide if metformin isn’t enough to help reach your blood sugar goals. 

However, most healthcare providers will recommend starting with just metformin first.

Due to the potential effectiveness of combining glipizide and metformin, the combination is available as a prescription with the generic name of ‘metaglip.’ The maximum dose of glipizide/metformin is 20 mg glipizide/2000 mg metformin.

If you have kidney disease or liver disease, your healthcare provider might not recommend metformin and/or glipizide, depending on the severity of the disease. 

Natural alternatives to glipizide and metformin

1) Diet and lifestyle changes

While it’s not a supplement, there’s no substitute for practicing healthy lifestyle habits. While metformin and glipizide can be effective, they’ll be even more effective if you aim to eat a healthy diet and stay active.

Eating a diet low in added sugars, focusing on fiber-rich carbohydrates, eating adequate amounts of protein, and including healthy fats in your diet are natural ways to help promote healthy blood sugar levels, whether you’re taking prescription diabetes medications or not.

2) Berberine

Berberine is a compound in some plants like European barberry, goldenseal, goldthread, Oregon grape, Phellodendron, and tree turmeric. 

Berberine is most well-known for its blood sugar-lowering properties by supporting healthy blood sugar levels and improving insulin sensitivity.

A pilot study compared berberine and metformin for their ability to help treat symptoms of type 2 diabetes. 

The researchers found that berberine produced identical results as metformin in terms of improving blood glucose metabolism, which makes berberine a top natural alternative to glipizide and metformin.

In addition, a small study on people with metabolic syndrome (a condition that can lead to type 2 diabetes) found that berberine improved insulin sensitivity and reduced the waist circumference of participants.

3) Inositol

Inositol is a vitamin-like substance that acts like insulin, helping to lower blood glucose levels. Myo- and D-chiro inositol have been studied for their ability to improve insulin sensitivity and are often recommended for women suffering from polycystic ovary syndrome (PCOS), a condition often linked with insulin resistance.

Inositol can improve blood sugar levels in people with insulin-resistant PCOS and diabetes, and it’s even been studied for the potential to reduce the incidence of type 2 diabetes in children.

Inositol has been studied in direct comparison with metformin in insulin-resistant women. 

Both metformin and myo-inositol were found to have similar positive effects on insulin levels, fasting blood sugar, and hormone levels.

Inositol can be found in different blends (a mix of D-chiro and myo-inositol, plain D-chiro inositol, or plain myo-inositol), dosages, and forms, including powders and capsules to be used as a natural alternative to metformin and glipizide.

4) N-acetyl-cysteine (NAC)

N-acetyl-cysteine is used by your body to make antioxidants, substances that help fight inflammation and cell damage. 

According to a small study, NAC improves insulin sensitivity in women with insulin resistance. When insulin sensitivity is improved, more blood sugar can enter your cells where it’s needed to lower the amount of sugar in your blood. 

Another study found that NAC improved glucose intolerance in diabetes-prone mice.

NAC also acts as an antioxidant and helps to fight inflammation. Type 2 diabetes is thought to be partly caused by inflammation, which is another reason it might be helpful as a natural alternative to metformin and glipizide.

Conclusion

Glipizide and metformin are both oral medications used to treat type 2 diabetes.

Glipizide is a sulfonylurea, and metformin is a biguanide, so they work in different ways to lower your blood sugar levels.

The main differences between glipizide vs metformin are their method of action and their potential side effects/risks (mainly that glipizide can cause hypoglycemia and metformin doesn’t).

Metformin and glipizide are often taken together to maximize their effectiveness at lowering blood sugar levels.

Natural alternatives to metformin and glipizide include healthy lifestyle habits, berberine, inositol, and N-acetyl-cysteine.

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