Linagliptin / Metformin Side Effects

Medically reviewed by Drugs.com. Last updated on Feb 22, 2025.

Applies to linagliptin / metformin: oral tablet, oral tablet extended release.

Important warnings This medicine can cause some serious health issues

Oral route (tablet; tablet, extended release)

Lactic acidosis can occur due to metformin accumulation during treatment with linagliptin/metformin hydrochloride, and case reports of death, hypothermia, hypotension, and resistant bradyarrhythmias have been reported.

The risk of lactic acidosis is increased with renal impairment, concomitant cationic drugs (eg, topiramate), age 65 years or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Onset is often subtle with symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain.

Laboratory abnormalities include elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL.

If lactic acidosis is suspected, immediately discontinue therapy, hospitalize patient, and promptly start hemodialysis.

Other side effects

Some side effects of linagliptin / metformin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common side effects

• diarrhea
• excess air or gas in the stomach or intestines
• feeling of fullness
• heartburn
• lack or loss of strength
• muscle aches
• passing gas
• sore throat
• stuffy or runny nose

Incidence not known

• cough
• decreased appetite
• difficulty with moving
• flaking and falling off of the skin
• hives or welts, itching, or skin rash
• muscle aching or cramping
• muscle pains or stiffness
• redness of the skin
• swollen joints

Serious side effects

Along with its needed effects, linagliptin / metformin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking linagliptin / metformin:

Less common side effects

• anxiety
• blurred vision
• chills
• cold sweats
• confusion
• cool, pale skin
• depression
• dizziness
• fast heartbeat
• headache
• increased hunger
• loss of consciousness
• nausea
• nightmares
• seizures
• shakiness
• slurred speech
• unusual tiredness or weakness

Incidence not known

• bloating
• constipation
• darkened urine
• fainting spells
• fever
• indigestion
• irregular heartbeat
• large, hard skin blisters
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• pains in the stomach, side, or abdomen, possibly radiating to the back
• severe joint pain
• vomiting
• yellow eyes or skin

For healthcare professionals

Applies to linagliptin / metformin: oral tablet, oral tablet extended release.

General adverse events

The most commonly reported adverse events included nasopharyngitis and diarrhea.^[Ref]

Metabolic

Linagliptin-Metformin:

• Frequency not reported: Hypoglycemia

Linagliptin:

• Common (1% to 10%): Hypertriglyceridemia, hyperlipidemia, weight increased

Metformin:

• Very rare (less than 0.01%): Lactic acidosis, vitamin B12 deficiency^[Ref]

Hypoglycemia was more commonly reported in patients receiving the combination linagliptin / metformin plus a sulfonylurea compared with those receiving metformin plus a sulfonylurea (22.9% vs 14.8%; n=792).^[Ref]

Gastrointestinal

Linagliptin-Metformin:

• Common (1% to 10%): Decreased appetite, diarrhea, nausea, vomiting
• Uncommon (0.1% to 1%): Increased blood amylase
• Postmarketing reports: Mouth ulceration

Linagliptin:

• Common (1% to 10%): Constipation, diarrhea
• Frequency not reported: Pancreatitis
• Postmarketing reports: Acute pancreatitis, including fatal pancreatitis, stomatitis

Metformin:

• Very common (10% or more): Diarrhea, nausea, vomiting, abdominal pain, decreased appetite
• Common (1% to 10%): Constipation
• Frequency not reported: Flatulence, indigestion^[Ref]

Gastrointestinal events such as nausea, vomiting, diarrhea, decreased appetite, and abdominal pain occur most frequently during initiation of therapy and resolve spontaneously in most cases.

During clinical trials, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure in patients receiving linagliptin compared with 3.7 cases per 10,000 patient year exposure in those receiving active comparator (sulfonylurea). Following completion of clinical trials, 3 additional cases of pancreatitis were reported among those receiving linagliptin. Postmarketing reports of acute pancreatitis, including fatalities, have been received.^[Ref]

Hypersensitivity

Linagliptin-Metformin:

• Rare (less than 0.1%): Drug hypersensitivity

Linagliptin

• Postmarketing reports: Serious hypersensitivity reactions^[Ref]

Serious hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions have been reported postmarketing in patients treated with linagliptin. These reactions have occurred within the first 3 months, with some occurring after the first dose.^[Ref]

Respiratory

• Common (1% to 10%): Nasopharyngitis (6.3%),
• Uncommon (0.1% to 1%): Cough
• Common (1% to 10%): Nasopharyngitis, cough
• Common (1% to 10%): Nasopharyngitis^[Ref]

Linagliptin-Metformin

Linagliptin

Metformin

Dermatologic

Linagliptin-Metformin:

• Uncommon (0.1% to 1%): Pruritus
• Postmarketing reports: Angioedema, urticaria, rash

Metformin:

• Very rare (less than 0.01%): Skin reactions such as erythema, pruritus, and urticaria

Linagliptin:

• Postmarketing reports: Bullous pemphigoid^[Ref]

Postmarketing reports of bullous pemphigoid requiring hospitalization have been reported with dipeptidyl peptidase-4 (DPP-4) inhibitors use. These case typically recovered with topical or systemic immunosuppressive treatment and discontinuation of DPP-4 inhibitor.^[Ref]

Hematologic

• Very rare (less than 0.01%): Megaloblastic anemia^[Ref]

Metformin

Hepatic

Metformin:

• Very rare (less than 0.01%): Hepatitis, liver function test abnormalities
• Postmarketing reports: Cholestatic, hepatocellular, and mixed hepatocellular liver injury^[Ref]

Musculoskeletal

Linagliptin:

• Frequency not reported: Myalgia, arthralgia
• Postmarketing reports: Severe and disabling arthralgia, rhabdomyolysis^[Ref]

Between October 2006 and December 2013, thirty-three cases of severe arthralgia have been reported to the FDA Adverse Event Reporting System Database. Each case involved the use of 1 or more dipeptidyl peptidase-4 (DPP-4) inhibitor. In all cases, substantial reduction in prior activity level was reported, 10 patients were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 month of starting therapy, in 23 cases symptoms resolved less than 1 month after discontinuation. A positive rechallenge was reported in 8 cases, with 6 cases involving use of a different DPP-4 inhibitor. Sitagliptin had the greatest number of cases reported (n=28) followed by saxagliptin (n=5), linagliptin (n=2), alogliptin (n=1), and vildagliptin (n=2).^[Ref]

Nervous system

Metformin:

• Common (1% to 10%): Taste disturbance^[Ref]

Genitourinary

Linagliptin:

• Common (1% to 10%): Urinary tract infection,^[Ref]

Psychiatric

Linagliptin:

• Common (1% to 10%): Headache

Metformin:

• Common (1% to 10%): Headache^[Ref]

Further information

Linagliptin/metformin side effects can vary depending on the individual. Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Note: Medication side effects may be underreported. If you are experiencing side effects that are not listed, submit a report to the FDA by following this guide.

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