Metformin / Pioglitazone

Metformin/pioglitazone tablets are used alongside diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus.

• Actoplus Met tablets are approved for improving blood sugar control in adults with type 2 diabetes as an adjunct to diet and exercise
• Pioglitazone and metformin hydrochloride tablets (including all generic versions listed) are approved for the same indication in adults with type 2 diabetes
• This combination is intended for use when treatment with both pioglitazone and metformin is appropriate
• None of these products are recommended for type 1 diabetes mellitus or diabetic ketoacidosis

This tablet pairs two blood-sugar-lowering medicines with different but complementary mechanisms. Pioglitazone belongs to a class called thiazolidinediones — it activates a receptor in fat, muscle, and liver cells called PPARγ, which makes those cells more responsive to insulin. As a result, more glucose is absorbed out of the bloodstream and the liver releases less glucose on its own. Metformin works mainly by reducing how much sugar the liver produces and releases, slowing glucose absorption from the gut, and improving the body's overall sensitivity to insulin — without causing the pancreas to secrete extra insulin.

Because pioglitazone depends on insulin already being present in the body to work, it is not effective in type 1 diabetes. Metformin on its own does not typically cause low blood sugar, but the combination can lower blood sugar further when used with insulin or certain other diabetes medicines.

These tablets are taken by mouth, with meals, to minimize the stomach discomfort that metformin can cause. The starting dose and how often you take it depends on your current diabetes treatment — your prescriber will individualize the regimen and adjust it gradually based on how your blood sugar responds. If you miss a dose, do not take a double dose to make up for it.

• Take with food every time
• Liver and kidney function should be checked before starting
• Your prescriber may stop this medicine temporarily before surgery, imaging procedures with contrast dye, or during illness with restricted food and fluid intake

The most common side effects reported in clinical trials include:

• Upper respiratory tract infections (cold-like symptoms)
• Swelling in the hands, feet, or legs (edema)
• Diarrhea
• Headache
• Weight gain
• Sinusitis
• Muscle aches (myalgia)

Serious reactions — including signs of lactic acidosis (muscle pain, trouble breathing, stomach pain, unusual tiredness or weakness, feeling cold), heart failure (rapid weight gain, swelling, shortness of breath), liver injury (jaundice, dark urine, right-side abdominal pain), or bladder problems (blood in urine, pain when urinating) — require immediate medical attention.

• Lactic acidosis (metformin): A rare but potentially fatal buildup of lactic acid in the blood. Risk is highest in people with kidney impairment, liver disease, heart failure, those aged 65+, heavy alcohol drinkers, and those undergoing contrast imaging or surgery. Symptoms include muscle pain, stomach pain, trouble breathing, unusual drowsiness, or feeling cold. Stop the medicine and call 911 or go to an emergency room immediately.
• Heart failure (pioglitazone): Pioglitazone causes dose-related fluid retention that can trigger or worsen heart failure. This medicine is contraindicated in NYHA Class III or IV heart failure. Watch for sudden weight gain, swelling, or shortness of breath after starting or increasing the dose.
• Liver injury: Postmarketing reports of serious, sometimes fatal, liver failure exist. Get liver tests before starting and contact your doctor if you notice fatigue, jaundice, or dark urine.
• Bladder cancer: Pioglitazone may be associated with a possible increased risk of bladder cancer. Do not use this medicine if you have active bladder cancer; use with caution if you have a history of it.
• Bone fractures: An increased rate of fractures has been reported in women taking pioglitazone. Bone health monitoring is recommended.
• Macular edema: Postmarketing reports of fluid buildup in the eye exist. Report any sudden vision changes promptly.
• Vitamin B12 deficiency: Metformin can lower vitamin B12 levels over time. Blood tests should be checked periodically.

Several medicines and substances can interact with metformin/pioglitazone in clinically important ways:

• Gemfibrozil (cholesterol medicine): Significantly raises pioglitazone blood levels — dose must be reduced when used together
• Rifampin (antibiotic): Can lower pioglitazone levels, possibly reducing blood sugar control
• Topiramate and other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide): Raise the risk of lactic acidosis and may lower pioglitazone levels
• Ranolazine, vandetanib, dolutegravir, cimetidine: Slow the kidney's removal of metformin, raising the risk of metformin accumulation and lactic acidosis
• Insulin or sulfonylureas (e.g., glipizide, glyburide): Combining with this tablet raises the risk of hypoglycemia (low blood sugar)
• Alcohol: Potentiates metformin's effect on lactic acid metabolism — avoid excessive intake
• Blood-sugar-raising drugs (thiazide diuretics, corticosteroids, estrogens, oral contraceptives, phenytoin, and others): Can reduce the effectiveness of this combination
• Iodinated contrast agents (used in CT scans and other imaging): May impair kidney function and trigger lactic acidosis — this medicine may need to be stopped before and restarted only after kidney function is confirmed stable

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Do not take this medicine if you have NYHA Class III or IV heart failure, severe kidney impairment (eGFR below 30 mL/min), a history of serious allergic reaction to pioglitazone or metformin, or active metabolic acidosis including diabetic ketoacidosis
• Tell your doctor about any kidney problems — kidney function (eGFR) must be checked before starting and monitored at least yearly
• Tell your doctor about any liver disease or abnormal liver blood tests — this medicine is not recommended in hepatic impairment
• Tell your doctor if you have ever had bladder cancer — pioglitazone should not be used with active bladder cancer
• Older adults (65+) face a higher risk of lactic acidosis; kidney function should be checked more frequently
• This medicine has not been proven safe or effective in children and is not recommended for pediatric patients
• If you are pregnant or trying to become pregnant, discuss the risks of poorly controlled diabetes versus medication exposure with your prescriber — data on use during pregnancy are limited
• Metformin passes into breast milk in small amounts; discuss breastfeeding with your doctor before taking this combination
• Premenopausal women who are not using birth control should know that pioglitazone may trigger ovulation and increase the risk of unintended pregnancy
• If you have mitochondrial diseases (such as MELAS syndrome), this medicine is generally not recommended

If more metformin than prescribed is taken, lactic acidosis occurred in about 32% of reported overdose cases — this is a medical emergency. Metformin can be removed from the body by hemodialysis (a kidney-filtration procedure used in hospitals). If an overdose is suspected, call Poison Control at 1-800-222-1222 or go to an emergency room immediately.

Pioglitazone reduces insulin resistance in the body, leading to lower blood glucose levels, lower insulin levels in the blood, and lower HbA1c (a measure of average blood sugar over about 3 months). In clinical studies, pioglitazone also decreased triglyceride levels and increased HDL ("good") cholesterol, though effects on LDL and total cholesterol were inconsistent. Metformin lowers both fasting and after-meal blood glucose levels without stimulating extra insulin release from the pancreas, meaning it does not on its own cause hypoglycemia in most people.

When taken as a combination tablet, the absorption of both pioglitazone and metformin is equivalent to taking the two medicines separately. Taking the tablet with food does not significantly change the total amount of pioglitazone absorbed; for metformin, food slightly lowers the peak blood level but does not change the total amount absorbed overall. Pioglitazone is extensively metabolized in the liver (mainly by an enzyme called CYP2C8) into active breakdown products, and is excreted primarily in bile and feces; its half-life (the time it takes for half the drug to leave the body) ranges from about 3 to 7 hours for the parent drug and up to 16 to 24 hours for its active metabolites. Metformin is not broken down by the liver at all — it is excreted unchanged by the kidneys, which is why kidney function is so critical; it reaches steady-state levels in the blood within 24 to 48 hours.

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