Short answer: In the label's 24-week trial of Actoplus Met 15/850 mg twice daily, side effects in at least 5% were diarrhea (9.0% vs 2.6% on pioglitazone alone and 15.3% on metformin alone) and headache (5.5% vs 2.6% and 4.8%). Pioglitazone also causes dose-related swelling and weight gain. Actoplus Met has a boxed warning for congestive heart failure (pioglitazone) and lactic acidosis (metformin).
What Actoplus Met is approved for: Actoplus Met combines pioglitazone, a thiazolidinedione, with metformin, a biguanide. It is approved, along with diet and exercise, to improve blood sugar control in adults with type 2 diabetes (section 1). It is not recommended for type 1 diabetes or diabetic ketoacidosis.
Source
ACTOPLUS MET (pioglitazone and metformin hydrochloride) tablets, for oral use, prescribing information and Medication Guide. Takeda Pharmaceuticals America. DailyMed, version published August 24, 2026. DailyMed setid 42e49120-6f3f-11db-9fe1-0800200c9a66
WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS
Heart failure: thiazolidinediones, including the pioglitazone in Actoplus Met, cause or worsen congestive heart failure in some people. After starting and after dose increases, people are watched closely for fast weight gain, shortness of breath or swelling, and stopping it or lowering the pioglitazone dose is considered if heart failure develops. It is not recommended with symptomatic heart failure, and starting it is contraindicated in NYHA Class III or IV heart failure. Lactic acidosis: metformin-associated lactic acidosis reported after approval has caused death, low body temperature, low blood pressure and slow heart rhythms that resist treatment, often starting with vague symptoms such as feeling unwell, muscle aches, trouble breathing, sleepiness and abdominal pain. Risk factors include kidney impairment, certain drugs such as topiramate, age 65 or older, contrast scans, surgery, low-oxygen states, heavy alcohol use, liver impairment and mitochondrial diseases. If it is suspected, Actoplus Met is stopped immediately and supportive care started in a hospital; prompt hemodialysis is recommended.
These are the label's own numbers from the Adverse Reactions section. Where the label compares with placebo (a dummy treatment), both columns are shown, so you can see how much more often a reaction happened on Actoplus Met.
| Adverse event | ACTOPLUS MET 15/850 mg Twice Daily N=201 | Pioglitazone 15 mg Twice Daily N=190 | Metformin 850 mg Twice Daily N=209 |
|---|---|---|---|
| Diarrhea | 9.0 | 2.6 | 15.3 |
| Headache | 5.5 | 2.6 | 4.8 |
% of patients; there was no placebo group. Abdominal pain was 2.0% on Actoplus Met, 1.6% on pioglitazone and 3.3% on metformin.
| Trial and event | Comparison arm | Pioglitazone + Metformin arm |
|---|---|---|
| 16-week placebo-controlled (N=160 vs 168): Edema | Placebo + Metformin: 2.5 | Pioglitazone 30 mg + Metformin: 6.0 |
| 16-week placebo-controlled: Headache | Placebo + Metformin: 1.9 | Pioglitazone 30 mg + Metformin: 6.0 |
| 24-week 30 mg vs 45 mg (N=411 vs 416): Upper Respiratory Tract Infection | Pioglitazone 30 mg + Metformin: 12.4 | Pioglitazone 45 mg + Metformin: 13.5 |
| 24-week 30 mg vs 45 mg: Edema | Pioglitazone 30 mg + Metformin: 5.8 | Pioglitazone 45 mg + Metformin: 13.9 |
| 24-week 30 mg vs 45 mg: Headache | Pioglitazone 30 mg + Metformin: 5.4 | Pioglitazone 45 mg + Metformin: 5.8 |
| 24-week 30 mg vs 45 mg: Weight Increased | Pioglitazone 30 mg + Metformin: 2.9 | Pioglitazone 45 mg + Metformin: 6.7 |
% of patients. Edema combines leg swelling, general swelling, pitting swelling and fluid retention. The 16-week trial compared with placebo; the 24-week trial compared two pioglitazone doses without placebo.
| Adverse event | Placebo N=2,633 | Pioglitazone N=2,605 |
|---|---|---|
| Hypoglycemia | 18.8 | 27.3 |
| Edema | 15.3 | 26.7 |
| Cardiac Failure | 6.1 | 8.1 |
| Pain in Extremity | 5.7 | 6.4 |
| Back Pain | 5.1 | 5.5 |
| Chest Pain | 5.0 | 5.1 |
% of patients; mean follow-up 34.5 months in people with type 2 diabetes and blood vessel disease.
Pioglitazone alone vs placebo (Table 2): upper respiratory infection 13.2% vs 8.5%, headache 9.1% vs 6.9%, sinusitis 6.3% vs 4.6%, muscle pain 5.4% vs 2.7%, and sore throat 5.1% vs 0.8%.
Heart failure events added to metformin (Table 6): 0.6% on pioglitazone 30 mg vs 0 on placebo over 16 weeks, and 0.2% on 45 mg over 24 weeks; none were fatal. In PROactive, heart failure led 1.3% on pioglitazone vs 0.6% on placebo to stop.
In six pooled pioglitazone trials, stopping for side effects was 4.5% vs 5.8% on comparators. In PROactive it was 9.0% vs 7.7%.
In PROactive, bone fractures in women were 5.1% on pioglitazone vs 2.5% on placebo, mostly of the lower limb and lower arm, with no increase in men.
In PROactive, bladder cancer was diagnosed in 0.54% on pioglitazone vs 0.19% on placebo. Over 13 years of trial and follow-up, rates did not differ. Observational studies disagree.
In metformin trials of 29 weeks, previously normal vitamin B12 fell below normal in about 7% of people.
The Warnings and Precautions part of the label lists these. Each line gives the label's heading and what it means in plain words.
Congestive heart failure. The first boxed-warning risk. Pioglitazone can cause dose-related fluid retention, most often with insulin, which can cause or worsen heart failure. People are watched for symptoms, and stopping or lowering the pioglitazone dose is considered if heart failure develops.
Lactic acidosis. The second boxed-warning risk. Actoplus Met is not used with an eGFR below 30, and starting it at 30 to 45 is not recommended. eGFR is checked at least yearly. It is stopped around some iodinated contrast scans, paused while food and fluids are restricted, stopped in shock, heart attack, sepsis or low-oxygen states, avoided with liver disease, and not recommended with mitochondrial diseases.
Edema. Swelling was more frequent on pioglitazone than placebo and is dose-related. Actoplus Met is used with caution in people with swelling or at risk of heart failure.
Low blood sugar with insulin or a sulfonylurea. A lower dose of insulin or a medicine that makes the body release insulin may be needed with Actoplus Met.
Hepatic effects. Fatal and non-fatal liver failure has been reported with pioglitazone after approval. Liver tests are taken before starting and checked promptly if symptoms appear; Actoplus Met is interrupted if ALT is above three times normal and stays abnormal or worsens.
Urinary bladder tumors. Pioglitazone may be linked to bladder tumors. Actoplus Met is not used with active bladder cancer, and benefits and risks are weighed with a past history of bladder cancer.
Fractures. Pioglitazone raised fractures in women in PROactive. Fracture risk and bone health are considered, especially in women.
Macular edema. Swelling at the back of the eye has been reported with pioglitazone, sometimes with blurred vision. Regular eye exams are advised, and visual symptoms are referred to an eye doctor.
Vitamin B12 deficiency. Metformin may lower vitamin B12. Blood counts are measured yearly and vitamin B12 every 2 to 3 years.
From the Medication Guide that comes with Actoplus Met:
Dose Track has a side-effect log. Each entry records the symptom, a severity (none, mild, moderate, severe or life-threatening), the date and an optional note, and can be tied to a specific dose or logged on its own. The history screen shows what you logged over time, which makes it easier to tell your prescriber when a reaction started and whether it is easing. The app records what you enter; it does not judge whether a symptom is serious. For anything on the label's call-your-doctor list, call your doctor.
This page is what the FDA label says, in plain words. It is not medical advice. Follow your prescriber, and ask them or your pharmacist about anything here.