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Metformin / pioglitazone Side Effects

Not all side effects for metformin / pioglitazone may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to metformin / pioglitazone: oral tablet, oral tablet extended release

In addition to its needed effects, some unwanted effects may be caused by metformin / pioglitazone. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking metformin / pioglitazone:

More common
  • Bladder pain
  • bloody or cloudy urine
  • difficult, burning, or painful urination
  • frequent urge to urinate
  • lower back or side pain
  • swelling of the face, fingers, feet, or lower legs
  • weight gain
Less common
  • Pain or swelling in the arms or legs without any injury
  • pale skin
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • Abdominal or stomach discomfort
  • anxiety
  • blurred vision
  • chills
  • cold sweats
  • coma
  • confusion
  • cool, pale skin
  • decreased appetite
  • depression
  • diarrhea
  • dizziness
  • fast heartbeat
  • fast, shallow breathing
  • general feeling of discomfort
  • headache
  • increased hunger
  • muscle pain or cramping
  • nausea
  • nervousness
  • nightmares
  • seizures
  • shakiness
  • shortness of breath
  • sleepiness
  • slurred speech

Some of the side effects that can occur with metformin / pioglitazone may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Body aches or pain
  • cough
  • difficulty with breathing
  • ear congestion
  • fever, sneezing, or sore throat
  • loss of voice
  • runny nose
  • stuffy nose

For Healthcare Professionals

Applies to metformin / pioglitazone: oral tablet, oral tablet extended release


Common (1% to 10%): Edema

Very common (10% or more): Edema (26.7%)
Common (1% to 10%): Cardiac failure, chest pain[Ref]

Thiazolidinediones, including pioglitazone can cause dose-related fluid retention which can cause or exacerbate congestive heart failure in some patients. Combination with insulin and use in patients with NYHA Class I and II congestive heart failure may increase risk.[Ref]


Very common (10% or more): Abdominal pain, diarrhea, loss of appetite, nausea, vomiting
Uncommon (0.1% to 1%): Flatulence

Very common (10% or more): Abdominal pain, diarrhea, loss of appetite, nausea, vomiting[Ref]

Gastrointestinal events occur most frequently during initiation of therapy and resolve spontaneously in most cases.[Ref]


Common (1% to 10%): Anemia
Very rare (less than 0.01%): Vitamin B12 absorption decreased, lactic acidosis

Very rare (less than 0.01%): Vitamin B12 absorption decreased, lactic acidosis[Ref]


Common (1% to 10%): Weight increased

Very common (10% or more): Hypoglycemia (27.3%)
Common (1% to 10%): Weight gain[Ref]

Mean weight increase in patients receiving pioglitazone monotherapy for 1 year was 2 to 3 kg. In combination with metformin, mean weight increase over 1 year was 1.5 kg. The mechanism of weight gain is unclear, but probably involves a combination of fluid retention and fat accumulation.[Ref]


Common (1% to 10%): Upper respiratory infection
Uncommon (0.1% to 1%): Sinusitis

Common (1% to 10%): Upper respiratory infection, pharyngitis
Uncommon (0.1% to 1%): Sinusitis[Ref]

Nervous system

Common (1% to 10%): Hypoesthesia, headache, taste disturbance
Uncommon (0.1% to 1%): Insomnia

Common (1% to 10%): Taste disturbance

Common (1% to 10%): Hypoesthesia, headache[Ref]


Visual disturbances have been reported early in treatment and may be related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens. Macular edema has been reported postmarketing in patients taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, although some were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at time of diagnosis. Some patients improved with drug discontinuation.[Ref]

Common (1% to 10%): Visual disturbances
Postmarketing reports: Macular edema

Common (1% to 10%): Visual disturbances
Frequency not reported: Macular edema[Ref]


Very rare (less than 0.01%): Erythema, pruritus, urticaria

Very rare (less than 0.01%): Erythema, pruritus, urticaria[Ref]


Common (1% to 10%): Erectile dysfunction[Ref]


The most commonly reported adverse events included upper respiratory tract infection, edema, diarrhea, headache, and weight gain.[Ref]


There have been postmarketing reports of hepatic failure, including fatalities, in patients taking pioglitazone. The reports contain insufficient information to establish causality.[Ref]

Frequency not reported: Hepatitis, alanine aminotransferase increased, abnormal liver function tests

Frequency not reported: Hepatitis, abnormal liver function tests

Frequency not reported: Alanine aminotransferase increased
Postmarketing reports: Hepatic failure[Ref]


In pooled analysis of bone fractures in 8100 patients receiving pioglitazone and 7400 receiving comparator treatment; a higher rate of fractures was observed in women receiving pioglitazone (2.6% versus 1.7%).[Ref]

Common (1% to 10%): Bone fracture, arthralgia

Common (1% to 10%): Bone fracture, myalgia, extremity pain, back pain
Uncommon (0.1% to 1%): Serum creatine phosphokinase elevations[Ref]


According to a 5-year interim report of an ongoing 10-year observational cohort study, there was a non-significant increase in the risk of bladder cancer among patients exposed to pioglitazone compared to subjects never exposed. The duration of exposure was associated with an increased risk. For patients taking pioglitazone longer than 12 months, the relative risk of developing bladder cancer in any given year increased by 40% described as 10 cases in 10,000 patients with pioglitazone compared with 7 cases in 10,000 patients without pioglitazone.[Ref]

Uncommon (0.1% to 1%): Bladder cancer

Uncommon (0.1% to 1%): Bladder cancer[Ref]


Common (1% to 10%): Hematuria[Ref]


Postmarketing reports: Hypersensitivity and allergic reactions (anaphylaxis, angioedema, and urticaria)

Postmarketing reports: Hypersensitivity and allergic reactions (anaphylaxis, angioedema, and urticaria)[Ref]


1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

2. "Product Information. Actoplus Met (metformin-pioglitazone)." Takeda Pharmaceuticals America, Lincolnshire, IL.

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This material does not endorse drugs, diagnose patients, or recommend therapy. This information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate safety, effectiveness, or appropriateness for any given patient. does not assume any responsibility for any aspect of healthcare administered with the aid of materials provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the substances you are taking, check with your doctor, nurse, or pharmacist.